Fused heterocyclic compounds as phosphodiesterases (PDEs) inhibitors

ABSTRACT

The present invention provides a compound which has the effect of PDE inhibition, and which is useful as an agent for preventing or treating schizophrenia or so on represented by the formula (I):

The present application is a national stage application filed under 35U.S.C. §371 of International Application No. PCT/US2011/041443, filedJun. 22, 2011, which claims the benefit of U.S. Provisional ApplicationNo. 61/358,121, filed Jun. 24, 2010, and claims the benefit of U.S.Provisional Application No. 61/422,845, filed Dec. 14, 2010.

TECHNICAL FIELD

The present invention relates to fused heterocyclic compounds.

BACKGROUND OF THE INVENTION

Phosphodiesterases (PDEs) are a superfamily of enzymes encoded by 21genes and subdivided into 11 distinct families according to structuraland functional properties. These enzymes metabolically inactivate theubiquitous intracellular second messengers, cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP); PDEsselectively catalyze the hydrolysis of the 3′-ester bond, forming theinactive 5′-monophosphate. On the basis of substrate specificity, thePDE families can be further classified into three groups: i) thecAMP-PDEs (PDE4, PDE7, PDE8), ii) the cGMP-PDEs (PDE5, PDE6 and PDE9),and iii) the dual-substrate PDEs (PDE1, PDE2, PDE3, PDE10 and PDE11).

The cAMP and cGMP are involved in the regulation of virtually everyphysiological process such as pro-inflammatory mediator production andaction, ion channel function, muscle relaxation, learning and memoryformation, differentiation, apoptosis, lipogenesis, glycogenolysis andgluconeogenesis. Especially, in neurons, these second messengers haveimportant role in the regulation of synaptic transmission as well as inneuronal differentiation and survival (Nat. Rev. Drug Discov. 2006, vol.5: 660-670). Regulation of these processes by cAMP and cGMP areaccompanied by activation of protein kinase A (PKA) and protein kinase G(PKG), which in turn phosphorylate a variety of substrates, includingtranscription factors, ion channels and receptors that regulate avariety of physiological processes. Intracellular cAMP and cGMPconcentrations seem to be temporally, spatially, and functionallycompartmentalized by regulation of adenyl and guanyl cyclases inresponse to extracellular signaling and their degradation by PDEs (Circ.Res. 2007, vol. 100(7): 950-966). PDEs provide the only means ofdegrading the cyclic nucleotides cAMP and cGMP in cells, thus PDEs playan essential role in cyclic nucleotide signaling. Thereby, PDEs could bepromising targets for various therapeutic drugs.

Phosphodiesterase 10A (PDE10A) was discovered in 1999 by threeindependent groups (Proc. Natl. Acad. Sci. USA 1999, vol. 96: 8991-8996,J. Biol. Chem. 1999, vol. 274: 18438-18445, Gene 1999, vol. 234:109-117). Expression studies have shown that PDE10A has the mostrestricted distribution within the all known PDE families; the PDE10AmRNA is highly expressed only in brain and testes (Eur. J. Biochem.1999, vol. 266: 1118-1127, J. Biol. Chem. 1999, vol. 274: 18438-18445).In the brain, mRNA and protein of PDE10A are highly enriched in mediumspiny neurons (MSNs) of the striatum (Eur. J. Biochem. 1999, vol. 266:1118-1127, Brain Res. 2003, vol. 985: 113-126). MSNs are classified intotwo groups: the MSN that express D₁ dopamine receptors responsible for adirect (striatonigral) pathway and the MSN that express D₂ dopaminereceptors responsible for an indirect (striatopallidal) pathway. Thefunction of direct pathway is to plan and execution, while indirectpathway is to act as a brake on behavioral activation. As PDE10Aexpresses in both MSNs, PDE10A inhibitors could activate both of thesepathways. The antipsychotic efficacy of current medications, D₂ orD₂/5-HT_(2A) antagonists, mainly derives from their activation of theindirect pathway in the striatum. As PDE10A inhibitors are able toactivate this pathway, this suggests that PDE10A inhibitors arepromising as antipsychotic drugs. The excessive D₂ receptor antagonismin the brain by D₂ antagonists causes problems of extrapyramidal sideeffects and hyperprolactinaemia. However the expression of PDE10A islimited to these striatal pathways in the brain, thus side effects byPDE10A inhibitors were expected to be weaker compared with current D₂antagonists. Regarding hyperprolactinaemia, PDE10A inhibitors wouldproduce no prolactin elevation due to lack of D₂ receptor antagonism inthe pituitary. Moreover, the presence of PDE10A in a direct pathwaymakes it likely that PDE10A inhibition will have some advantage overcurrent D₂ antagonists; the direct pathway is thought to promote desiredaction, and activation of this pathway by PDE10A inhibitors maycounteract extrapyramidal symptoms induced by excessive D₂ receptorantagonism. In addition, activation of this pathway could facilitatestriatal-thalamic outflow, promoting the execution of proceduralstrategies. Furthermore, enhancement of second messenger levels withoutblockade of dopamine and/or other neurotransmitter receptors may alsoprovide therapeutic advantages with fewer adverse side-effects comparedwith current antipsychotics (e.g., hyperprolactinaemia and weight gain).This unique distribution and function in the brain indicates that PDE10Arepresents an important new target for the treatment of neurological andpsychiatric disorders, in particular psychotic disorders likeschizophrenia.

As a phosphodiesterase (PDE) 10 inhibitor, compounds represented by theformulae:

were disclosed in WO2008/004117 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, compoundsrepresented by the formulae:

were disclosed in WO2010/0057121 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, compoundsrepresented by the formulae:

were also disclosed in WO2010/57126 Pamphlet.

Further as a phosphodiesterase (PDE) 10 inhibitor, a compoundrepresented by the formula:

wherein Z

was disclosed in WO2006/072828 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, a compoundrepresented by the general formula

was also disclosed in WO2008/001182 Pamphlet.

Further, as a phosphodiesterase (PDE) 10 inhibitor, a compoundrepresented by the general formula

was also disclosed in WO2010/090737 Pamphlet.

SUMMARY OF INVENTION Technical Problem

However, development of new phosphodiesterase (PDE) 10A inhibitors isfurther requested.

Solution to Problem

The present inventors discovered that a compound expressed by theformula (I) or a salt thereof (referred to as compound (I) in thisspecification) has a PDE 10A inhibitory action and after extensiveinvestigation, completed the present invention.

In this specification, the compound (I) or a prodrug thereof is alsoreferred to the compound of the present invention.

That is, the present invention provides the following.

[1] A compound represented by the formula (I):

whereinring A represents an optionally substituted 6-membered ring, any one ortwo of Z¹ to Z⁴ represent —N═, and the othersrepresent —CH═,Y represents an oxygen atom, a sulfur atom, an optionally substitutedmethylene group or —NR^(c)— wherein R^(c) represents a hydrogen atom ora substituent, andR represents

-   -   (1) a group represented by the formula:

-   -   -   wherein        -   R¹ is a phenyl group or a 5- to 10-membered heterocyclic            group, each of which is optionally substituted,        -   L is a sulfur atom, an oxygen atom, an optionally            substituted methylene group, —CO—, —NR^(a)—, —CH₂O—, —OCH₂—,            —NR^(a)COO—, —OCONR^(a)—, —NR^(a)CONR^(b)—, —NR^(a)COCH₂—,            —CH₂CONR^(a)—, —NR^(a)CO—, —CONR^(a)—,

-   -   -   -   wherein            -   R^(a) and R^(b) are the same or different and each is a                hydrogen atom or an optionally substituted C₁₋₆ alkyl                group, or

        -   L and R¹ in combination optionally fault an optionally            substituted bi- or tri-cyclic fused heterocyclic group, and            ring B¹ is a benzene ring, a pyridine ring, a pyrimidine            ring, a pyrazine ring or a pyridazine ring, each of which is            optionally substituted, or

    -   (2) a group represented by the formula:

-   -   -   wherein        -   R² is a phenyl group or a 5- to 10-membered heterocyclic            group, each of which is optionally substituted,        -   ring B² is a benzene ring, a pyridine ring, a pyrimidine            ring, a pyrazine ring or a pyridazine ring, each of which is            optionally substituted, and        -   ring D is an optionally further substituted 5- or 6-membered            ring,            provided that

-   3,3′-benzene-1,4-diylbis(1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one),

-   1-cyclohexyl-3-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,

-   3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,

-   3,3′-benzene-1,4-diylbis(1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one),    and

-   3-[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one    are excluded,    or a salt thereof.    [1′] The compound of the aforementioned [1], wherein R is    (1) a group represented by the formula:

wherein each symbol is as defined in the aforementioned [1], or(2) a group represented by the formula:

wherein ring B² is a benzene ring, a pyridine ring, a pyrimidine ring, apyrazine ring or a pyridazine ring, each of which is optionallysubstituted, andring D is an optionally further substituted 5- or 6-membered ring,R² is as defined in the aforementioned [1],provided that when ring B² is a benzene ring, ring D is not a benzenering,or a salt thereof.[1″] The compound of the aforementioned [1], wherein R is(1) a group represented by the formula:

-   -   wherein    -   R¹ is a phenyl group or a 5- to 10-membered heterocyclic group,        each of which is optionally substituted,    -   L is a sulfur atom, an oxygen atom, an optionally substituted        methylene group, —CO—, —NR^(a)—, —CH₂O—, —OCH₂—, —NR^(a)COO—,        —OCONR^(a)—, —NR^(a)CONR^(b)—, —NR^(a)COCH₂—, —CH₂CONR^(a)—,        —NR^(a)CO—, —CONR^(a)—,

-   -   -   wherein        -   R^(a) and R^(b) are as defined in the aforementioned [1], or

    -   L and R¹ in combination optionally form an optionally        substituted bi- or tri-cyclic fused heterocyclic group, and ring        B¹ is a benzene ring, a pyridine ring, a pyrimidine ring, a        pyrazine ring or a pyridazine ring, each of which is optionally        substituted,

    -   provided that when L is an oxygen atom, R¹ is not an optionally        substituted phenyl, or        (2) a group represented by the formula:

-   -   wherein each symbol is as defined in the aforementioned [1], or        a salt thereof.        [2] The compound of the aforementioned [1], wherein any one of        Z¹ to Z⁴ is —N═, and the others are —CH═,        or a salt thereof.        [3] The compound of the aforementioned [1], wherein the partial        structure of the formula (I):

is a group represented by the formula:

-   -   wherein    -   Y¹ is an optionally substituted methylene group or —NR^(c)—        wherein R^(c) is a hydrogen atom or a substituent, and    -   ring A¹ is an optionally substituted pyridine ring, or        a group represented by the formula:

-   -   wherein    -   Y² is —NR^(d)— wherein R^(d) is a substituent, and    -   ring A² is an optionally substituted pyridine ring,        or a salt thereof.        [4] The compound of the aforementioned [1], wherein L is an        oxygen atom, or —NR^(a)— wherein R^(a) is a hydrogen atom or an        optionally substituted C₁₋₆ alkyl group, or        L and R¹ in combination optionally form an optionally        substituted bi- or tri-cyclic fused heterocyclic group, or a        salt thereof.        [5] The compound of the aforementioned [3], wherein the partial        structure of formula (I):

is a group represented by the formula:

wherein ring A¹ and Y¹ are as defined in the aforementioned [3], or asalt thereof.[6] The compound of the aforementioned [3], wherein the partialstructure of formula of formula (I):

is a group represented by the formula:

whereinthe R³′″ represents a hydrogen atom, a halogen atom, an optionallysubstituted C₁₋₄ alkyl group, or an optionally substituted C₁₋₄ alkoxygroup, andY¹ is as defined in the aforementioned [3],or a salt thereof.[7] The compound of the aforementioned [3], wherein the partialstructure of formula (I):

is a group represented by the formula:

whereinR^(3a) and R^(3b) represent the same or different a hydrogen atom, ahalogen atom, cyano, an optionally substituted C₁₋₄ alkyl group or anoptionally substituted C₁₋₄ alkoxy group, andR⁴ represents an optionally substituted C₁₋₄ alkyl group, provided thatwhen one of R^(3a) and R^(3b) is a hydrogen atom, the other is not ahydrogen atom,or a salt thereof.[8] The compound of the aforementioned [1], wherein ring B¹ is anoptionally substituted benzene ring, or a salt thereof.[9] The compound of the aforementioned [1], wherein R¹ is a 5- to10-membered heterocyclic group which is optionally substituted, or asalt thereof.[10] The compound of the aforementioned [9], wherein the 5- to10-membered heterocyclic group which is optionally substituted is agroup represented by the formula:

wherein R^(x) represents a hydrogen atom or an optionally substitutedC₁₋₆ alkyl group,or a salt thereof.[11]1-Ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[12]1-Ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[13]1-Ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[14]6-Methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[15]1-Ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[16]1,7-Dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[17]1-Ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.[18] A medicament comprising the compound of the aforementioned [1], ora salt thereof.[19] The medicament of the aforementioned [18], which is aphosphodiesterase 10A inhibitor.[20] The medicament of the aforementioned [18], which is an agent forthe prophylaxis or treatment of schizophrenia.[21] A method for preventing or treating schizophrenia in a mammal,which comprises administering an effective amount of a compoundrepresented by the formula (I):

whereinring A represents an optionally substituted 6-membered ring, any one ortwo of Z¹ to Z⁴ represent —N═, and the others represent —CH═,Y represents an oxygen atom, a sulfur atom, an optionally substitutedmethylene group, or —NR^(c)— wherein R^(c) represents a hydrogen atom ora substituent, andR represents

-   -   (1) a group represented by the formula:

-   -   -   to wherein        -   R¹ is a phenyl group or a 5- to 10-membered heterocyclic            group, each of which is optionally substituted,        -   L is a sulfur atom, an oxygen atom, an optionally            substituted methylene group, —CO—, —NR^(a)—, —CH₂O—, —OCH₂—,            —NR^(a)COO—, —OCONR^(a)—, —NR^(a)CONR^(b)—, —NR^(a)COCH₂—,            —CH₂CONR^(a)—, —NR^(a)CO—, —CONR^(a)—,

-   -   -   -   wherein            -   R^(a) and R^(b) are the same or different and each is a                hydrogen atom or an optionally substituted C₁₋₆ alkyl                group, or

        -   L and R¹ in combination optionally form an optionally            substituted bi- or tri-cyclic fused heterocyclic group, and            ring B¹ is a benzene ring, a pyridine ring, a pyrimidine            ring, a pyrazine ring or a pyridazine ring, each of which is            optionally substituted, or

    -   (2) a group represented by the formula:

-   -   -   wherein        -   R² is a phenyl group or a 5- to 10-membered heterocyclic            group, each of which is optionally substituted,        -   ring B² is a benzene ring, a pyridine ring, a pyrimidine            ring, a pyrazine ring or a pyridazine ring, each of which is            optionally substituted, and        -   ring D is an optionally further substituted 5- or 6-membered            ring,            to the mammal.            [22] Use of a compound represented by the formula (I):

wherein each symbol is as defined above,or salt thereof for the production of an agent for the prophylaxis ortreatment of schizophrenia.[23] A compound represented by the formula (I):

wherein each symbol is as defined above,or salt thereof for use in the prophylaxis or treatment ofschizophrenia.[24] Use of a compound represented by the formula (I):

wherein each symbol is as defined above,or a salt thereof for use in the prophylaxis or treatment ofschizophrenia.[25] A compound represented by the formula (I′):

whereinring A represents an optionally substituted 6-membered ring, any one ortwo of Z¹ to Z⁴ represent —N═, and the others represent —CH═,Y represents an oxygen atom, a sulfur atom, an optionally substitutedmethylene group, or —NR^(c)— wherein R^(c) represents a hydrogen atom ora substituent, andR′ represents

-   -   (1) a group represented by the formula:

whereinR¹ is a phenyl group or a 5- to 10-membered heterocyclic group, each ofwhich is optionally substituted,L′ is a sulfur atom, —CO—, —NR^(a)—, —CH₂O—, —OCH₂—, —NR^(a)COO—,—OCONR^(a)—, —NR^(a)CONR^(b)—, —NR^(a)COCH₂—, —CH₂CONR^(a)—, —NR^(a)CO—,—CONR^(a)—,

whereinR^(a) and R^(b) are the same or different and each is a hydrogen atom oran optionally substituted C₁₋₆ alkyl group,R¹′ is an optionally substituted 5- to 10-membered heterocyclic group,orL and R¹ in combination optionally form a bi- or tri-cyclic fusedheterocyclic group which is optionally substituted by 1 to 3substitutents selected from (a) a halogen atom, (b) an optionallyesterified carboxy group, and(c) an optionally substituted alkyl group, andring B¹ is a benzene ring, a pyridine ring, a pyrimidine ring, apyrazine ring or a pyridazine ring, each of which is optionallysubstituted, or

-   -   (2) a group represented by the formula:

whereinR² is a phenyl group or a 5- to 10-membered heterocyclic group, each ofwhich is optionally substituted,ring B² is a benzene ring, a pyridine ring, a pyrimidine ring, apyrazine ring or a pyridazine ring, each of which is optionallysubstituted, andring D′ is optionally further substituted 5- or 6-membered heterocycle,or a salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows increase of cAMP (FIG. 1A) and cGMP (FIG. 1B) contents inthe mouse striatum by oral administration of compounds. Sixty min afteroral administration of the compounds, striatum was isolated from miceand then cAMP and cGMP contents were measured using EIA kits.

FIG. 2 shows inhibition of MK-801-induced hyperlocomotion by compoundsin mice. By orally administered 60 min before MK-801 (0.3 mg/kg, s.c.)treatment, compounds produced the inhibition of MK-801-inducedhyperlocomotion.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, unless otherwise specified, examples ofthe “halogen atom” include fluorine, chlorine, bromine and iodine.

In the present specification, unless otherwise specified, the term“optionally halogenated” or “halogeno” means the optionally presence ofone or more (e.g., 1 to 3) halogen atoms as substituents.

In the present specification, unless otherwise specified, examples ofthe “alkyl (group)” include a C₁₋₆ alkyl (group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkyl (group)” include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl and the like.

In the present specification, unless otherwise specified, the“optionally halogenated C₁₋₆alkyl (group)” means a C₁₋₆ alkyl (group)optionally substituted by halogen atom(s), and examples thereof includetrifluoromethyl and the like.

In the present specification, unless otherwise specified, examples ofthe “alkenyl (group)” include a C₂₋₆ alkenyl (group).

In the present specification, unless otherwise specified, examples ofthe “C₂₋₆ alkenyl (group)” include vinyl, 1-propen-1-yl, 2-propen-1-yl,isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like.

In the present specification, unless otherwise specified, examples ofthe “alkynyl (group)” include a C₂₋₆ alkynyl group. Examples of the“C₂₋₆ alkynyl (group)” include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl,4-pentyn-1-yl, 5-hexyn-1-yl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkyl-C₂₋₆ alkynyl (group)” include cyclopropylethynyland the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkyl (group)” include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryl (group)” include phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₇₋₁₆ aralkyl (group)” include benzyl, phenethyl, diphenylmethyl,1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl,4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl,4-biphenylylmethyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryl-C₂₋₆ alkenyl (group)” include styryl and the like.

In the present specification, unless otherwise specified, examples ofthe “carbocycle having 5 or 6 carbon atoms” include a C₅₋₆ cycloalkane(e.g., cyclopentane, cyclohexane), a C₅₋₆ cycloalkene (e.g.,cyclopentene, cyclohexene), a C₅₋₆ cycloalkadiene (e.g.,cyclopentadiene, cyclohexadiene) and a benzene ring.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₆ cycloalkane” include cyclopropane, cyclobutane, cyclohexaneand cyclopentane.

In the present specification, unless otherwise specified, examples ofthe “5- or 6-membered heterocycle” include a 5- or 6-memberedheterocycle containing, besides carbon atoms, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe “5- or 6-membered heterocycle containing, besides carbon atoms, 1 to4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom” include a pyrrolidine ring, a tetrahydrofuran ring, atetrahydrothiophene ring, a piperidine ring, a tetrahydropyran ring, amorpholine ring, a thiomorpholine ring, a piperazine ring, a furan ring,a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, athiazole ring, an isothiazole ring, an imidazole ring, a pyrazole ring,a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazolering, a furazan ring, a 1,2,3-thiadiazole ring, a 1,2,4-thiadiazolering, a 1,3,4-thiadiazole ring, a 1,2,3-triazole ring, a 1,2,4-triazolering, a tetrazole ring, a pyridine ring, a pyridazine ring, a pyrimidinering, a pyrazine ring, a triazine ring and the like.

In the present specification, unless otherwise specified, “heterocyclicgroup” (and the heterocyclic moiety of the substituent) is anon-aromatic heterocyclic group or a heteroaryl group (i.e., an aromaticheterocyclic group), and examples thereof include a 3- to 14-memberedheterocyclic group containing 1 to 5 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom. The “heterocyclicgroup” can be monocyclic, bicyclic or tricyclic.

In the present specification, unless otherwise specified, examples ofthe “3- to 14-membered heterocyclic group” include 3- to 14-memberedaromatic heterocyclic groups containing 1 to hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom, such as pyrrolyl(e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl,3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl (e.g.,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (e.g., 1-imidazolyl,2-imidazolyl, 4-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl,5-oxazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl,5-thiazolyl), triazolyl (e.g., 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl),oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl),thiadiazolyl (e.g., 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl),tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl(e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, isoindolyl (e.g.,1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl,6-isoindolyl, 7-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo[b]furanyl(e.g., 2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),benzo[c]furanyl (e.g., 1-benzo[c]furanyl, 4-benzo[c]furanyl,5-benzo[c]furanyl), benzo[b]thienyl (e.g., 2-benzo[b]thienyl,3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl,6-benzo[b]thienyl, 7-benzo[b]thienyl), benzo[c]thienyl (e.g.,1-benzo[c]thienyl, 4-benzo[c]thienyl, 5-benzo[c]thienyl), indazolyl(e.g., 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl,6-indazolyl, 7-indazolyl), benzimidazolyl (e.g., 1-benzimidazolyl,2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl),1,2-benzisoxazolyl (e.g., 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl,1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl),benzoxazolyl (e.g., 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl,6-benzoxazolyl, 7-benzoxazolyl), 1,2-benzisothiazolyl (e.g.,1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl,1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl,1,2-benzisothiazol-7-yl), benzothiazolyl (e.g., 2-benzothiazolyl,4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl),isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl,5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), phthalazinyl(e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), quinazolinyl(e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl,7-quinazolinyl, 8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl,5-quinoxalinyl, 6-quinoxalinyl), pyrazolo[1,5-a]pyridyl (e.g.,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl,pyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridine-7-yl),imidazo[1,2-a]pyridyl (e.g., imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl,imidazo[1,2-a]pyridin-8-yl) and the like; and

3- to 14-membered saturated or unsaturated non-aromatic heterocyclicgroups containing 1 to 5 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom, such as tetrahydrofuryl, oxazolidinyl,imidazolinyl (e.g., 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl),aziridinyl (e.g., 1-aziridinyl, 2-aziridinyl), azetidinyl (e.g.,1-azetidinyl, 2-azetidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl (e.g., 1-piperidyl,2-piperidyl, 3-piperidyl), azepanyl (e.g., 1-azepanyl, 2-azepanyl,3-azepanyl, 4-azepanyl), azocanyl (e.g., 1-azocanyl, 2-azocanyl,3-azocanyl, 4-azocanyl), azonanyl (e.g., 1-azonanyl, 2-azonanyl,3-azonanyl, 4-azonanyl, 5-azonanyl), piperazinyl (e.g.,1,4-piperazin-1-yl, 1,4-piperazin-2-yl), diazepinyl (e.g.,1,4-diazepin-1-yl, 1,4-diazepin-2-yl, 1,4-diazepin-5-yl,1,4-diazepin-6-yl), diazocanyl (e.g., 1,4-diazocan-1-yl,1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1,4-diazocan-6-yl,1,5-diazocan-1-yl, 1,5-diazocan-2-yl, 1,5-diazocan-3-yl),tetrahydropyranyl (e.g., tetrahydropyran-4-yl), morpholinyl (e.g.,4-morpholinyl), thiomorpholinyl (e.g., 4-thiomorpholinyl),2-oxazolidinyl, dihydrofuryl, dihydropyranyl, dihydroquinolyl,dihydroisoquinolyl (e.g., 3,4-dihydroisoquinolin-2-yl) and the like.

In the present specification, unless otherwise specified, examples ofthe “aromatic heterocyclic group” (and the aromatic heterocyclic moietyof the substituent) include those similar to the “3- to 14-memberedaromatic heterocyclic group containing 1 to 5 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom” exemplified above asthe aforementioned “heterocyclic group”.

In the present specification, unless otherwise specified, examples ofthe “non-aromatic heterocyclic group” (and the non-aromatic heterocyclicmoiety of the substituent) include those similar to the “3- to14-membered saturated or unsaturated non-aromatic heterocyclic groupcontaining 1 to 5 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom” exemplified above as the aforementioned“heterocyclic group”.

In the present specification, unless otherwise specified, examples ofthe “saturated heterocyclic group” (and the saturated heterocyclicmoiety of the substituent) include a saturated heterocyclic group, fromamong the aforementioned “non-aromatic heterocyclic groups”, andspecific examples thereof include tetrahydrofuryl, morpholinyl,thiomorpholinyl, piperidyl, pyrrolidinyl, piperazinyl and the like.

In the present specification, unless otherwise specified, examples ofthe “5- or 6-membered saturated heterocyclic group” (and the 5- or6-membered saturated heterocyclic moiety of the substituent) include a5- or 6-membered saturated heterocyclic group, from among theaforementioned “saturated heterocyclic groups”.

In the present specification, unless otherwise specified, examples ofthe “alkoxy (group)” include a C₁₋₆ alkoxy (group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkoxy (group)” include methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkyloxy (group)” include cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryloxy (group)” include phenyloxy, 1-naphthyloxy,2-naphthyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “C₇₋₁₆ aralkyloxy (group)” include benzyloxy, phenethyloxy and thelike.

In the present specification, unless otherwise specified, examples ofthe “alkyl-carbonyloxy (group)” include a C₁₋₆ alkyl-carbonyloxy(group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkyl-carbonyloxy (group)” include acetoxy, propionyloxy andthe like.

In the present specification, unless otherwise specified, examples ofthe “alkoxy-carbonyloxy (group)” include a C₁₋₆ alkoxy-carbonyloxy(group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkoxy-carbonyloxy (group)” include methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “mono-alkyl-carbamoyloxy (group)” include a mono-C₁₋₆alkyl-carbamoyloxy (group).

In the present specification, unless otherwise specified, examples ofthe “mono-C₁₋₆ alkyl-carbamoyloxy (group)” include methylcarbamoyloxy,ethylcarbamoyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “di-alkyl-carbamoyloxy (group)” include a di-C₁₋₆ alkyl-carbamoyloxy(group).

In the present specification, unless otherwise specified, examples ofthe “di-C₁₋₆ alkyl-carbamoyloxy (group)” include dimethylcarbamoyloxy,diethylcarbamoyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryl-carbonyloxy (group)” include benzoyloxy,naphthylcarbonyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₆₋₁₄ aryl-carbamoyl (group)” include phenylcarbamoyl,naphthylcarbamoyl and the like.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₆₋₁₄ aryl-carbamoyloxy (group)” includephenylcarbamoyloxy, naphthylcarbamoyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe heterocyclic moiety of the “heterocyclyl-oxy (group)” include thosesimilar to the aforementioned “heterocyclic group”. Specific examples ofthe “heterocyclyl-oxy (group)” include a 5- to 14-memberedheterocyclyl-oxy (group) containing 1 to 5 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe aromatic heterocyclic moiety of the “aromatic heterocyclyl-oxy(group)” include those similar to the “aromatic heterocyclic group”exemplified as the aforementioned “heterocyclic group”. Specificexamples of the “aromatic heterocyclyl-oxy (group)” include a 3- to14-membered aromatic heterocyclyl-oxy containing 1 to 5 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfonyloxy group” include methylsulfonyloxy,ethylsulfonyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “halogeno C₁₋₆ alkylsulfonyloxy group” includehalogenomethylsulfonyloxy, halogenoethylsulfonyloxy and the like.

In the present specification, unless otherwise specified, examples ofthe “alkylsulfanyl (group)” include a C₁₋₆ alkylsulfanyl (group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfanyl (group)” include methylsulfanyl, ethylsulfanyl,propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl,tert-butylsulfanyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkylsulfanyl (group)” include cyclopropylsulfanyl,cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl and thelike.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ arylsulfanyl (group)” include phenylsulfanyl,1-naphthylsulfanyl, 2-naphthylsulfanyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₇₋₁₆ aralkylsulfanyl (group)” include benzylsulfanyl,phenethylsulfanyl and the like.

In the present specification, unless otherwise specified, examples ofthe heterocyclic moiety of the “heterocyclyl-sulfanyl (group)” includethose similar to the aforementioned “heterocyclic group”. Specificexamples of the “heterocyclyl-sulfanyl (group)” include a 3- to14-membered heterocyclyl-sulfanyl (group) containing 1 to 5 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe “alkyl-carbonyl (group)” include a C₁₋₆ alkyl-carbonyl.

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkyl-carbonyl (group)” include acetyl, propionyl, pivaloyland the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkyl-carbonyl (group)” include cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryl-carbonyl (group)” include benzoyl, 1-naphthoyl,2-naphthoyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₇₋₁₆ aralkyl-carbonyl (group)” include phenylacetyl,3-phenylpropionyl and the like.

In the present specification, unless otherwise specified, examples ofthe heterocyclic moiety of the “heterocyclyl-carbonyl (group)” includethose similar to the above-mentioned “heterocyclic group”. Specificexamples thereof include a 3- to 14-membered heterocyclyl-carbonyl(group) containing 1 to 5 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom. More specific examples thereof includepicolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl,3-furoyl, 4-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl,aziridin-1-ylcarbonyl, aziridin-2-ylcarbonyl, azetidin-1-ylcarbonyl,azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl, pyrrolidin-2-ylcarbonyl,pyrrolidin-3-ylcarbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl,piperidin-3-ylcarbonyl, azepan-1-ylcarbonyl, azepan-2-ylcarbonyl,azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcarbonyl,azocan-2-ylcarbonyl, azocan-3-ylcarbonyl, azocan-4-ylcarbonyl,1,4-piperazin-1-ylcarbonyl, 1,4-piperazin-2-ylcarbonyl,1,4-diazepan-1-ylcarbonyl, 1,4-diazepan-2-ylcarbonyl,1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl,1,4-diazocan-1-ylcarbonyl, 1,4-diazocan-2-ylcarbonyl,1,4-diazocan-5-ylcarbonyl, 1,4-diazocan-6-ylcarbonyl,1,5-diazocan-1-ylcarbonyl, 1,5-diazocan-2-ylcarbonyl,1,5-diazocan-3-ylcarbonyl and the like.

In the present specification, unless otherwise specified, examples ofthe “optionally esterified carboxy (group)” include carboxy, optionallysubstituted alkoxy-carbonyl, optionally substituted C₆₋₁₄aryloxy-carbonyl, optionally substituted C₇₋₁₆ aralkyloxy-carbonyl,optionally substituted silyloxy-carbonyl (e.g.,trimethylsilyloxycarbonyl (TMS-O—CO—), triethylsilyloxycarbonyl(TES-O—CO—, tert-butyldimethylsilyloxycarbonyl (TBS-O—CO—),triisopropylsilyloxycarbonyl (TIPS-O—CO—),tert-butyldiphenylsilyloxycarbonyl (TBDPS-O—CO—)) and the like.

In the present specification, unless otherwise specified, examples ofthe “alkoxy-carbonyl (group)” include a C₁₋₆ alkoxy-carbonyl (group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkoxy-carbonyl (group)” include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryloxy-carbonyl (group)” include phenoxycarbonyl and thelike.

In the present specification, unless otherwise specified, examples ofthe “C₇₋₁₆ aralkyloxy-carbonyl (group)” include benzyloxycarbonyl,phenethyloxycarbonyl and the like.

In the present specification, unless otherwise specified, examples ofthe “alkylsulfonyl (group)” include a C₁₋₆ alkylsulfonyl (group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfonyl (group)” include methylsulfonyl, ethylsulfonyland the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkylsulfonyl (group)” include cyclopropylsulfonyl,cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and thelike.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ arylsulfonyl (group)” include phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.

In the present specification, unless otherwise specified, examples ofthe heterocyclic moiety of the “heterocyclyl-sulfonyl (group)” includethose similar to the aforementioned “heterocyclic group”. Specificexamples of the “heterocyclyl-sulfonyl (group)” include a 3- to14-membered heterocyclyl-sulfonyl (group) containing 1 to 5 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe “alkylsulfinyl (group)” include a C₁₋₆ alkylsulfinyl (group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfinyl (group)” include methylsulfinyl, ethylsulfinyland the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkylsulfinyl (group)” include cyclopropylsulfinyl,cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and thelike.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ arylsulfinyl (group)” include phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.

In the present specification, unless otherwise specified, examples ofthe heterocyclic moiety of the “heterocyclyl-sulfinyl (group)” includethose similar to the aforementioned “heterocyclic group”. Specificexamples of the “heterocyclyl-sulfinyl (group)” include a 3- to14-membered heterocyclyl-sulfinyl (group) containing 1 to 5 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe “alkyl-carbamoyl (group)” include a mono- or di-C₁₋₆alkyl-carbamoyl.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₁₋₆ alkyl-carbamoyl (group)” include methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl and the like.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-alkylamino (group)” include a mono- or di-C₁₋₆alkylamino (group).

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₁₋₆ alkylamino (group)” include methylamino,ethylamino, propylamino, dimethylamino, diethylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “alkyl-carbonylamino (group)” include a mono- or di-C₁₋₆alkyl-carbonylamino.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₁₋₆ alkyl-carbonylamino (group)” include acetylamino,propionylamino, pivaloylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “heterocyclyl (group)” of the “heterocyclyl-amino (group)” includethose similar to the above-mentioned “heterocyclic group”. Examples ofthe “heterocyclyl-amino (group)” include 2-pyridyl-amino and the like.

In the present specification, unless otherwise specified, examples ofthe “heterocyclyl-carbonyl” of the “heterocyclyl-carbonylamino (group)”include those similar to the above-mentioned “heterocyclyl-carbonyl”.Examples of the “heterocyclyl-carbonylamino (group)” includepyridyl-carbonylamino.

In the present specification, unless otherwise specified, examples ofthe “heterocyclyl (group)” of the “heterocyclyl-oxycarbonylamino(group)” include those similar to the above-mentioned “heterocyclicgroup”. Examples of the “heterocyclyl-oxycarbonylamino (group)” include2-pyridyl-oxycarbonylamino.

In the present specification, unless otherwise specified, examples ofthe “heterocyclyl (group)” of the “heterocyclyl-sulfonylamino (group)”include those similar to the above-mentioned “heterocyclic group”.Examples of the “heterocyclyl-sulfonylamino (group)” include2-pyridyl-sulfonylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “alkoxy-carbonylamino (group)” include a C₁₋₆ alkoxy-carbonylamino(group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkoxy-carbonylamino (group)” include methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and thelike.

In the present specification, unless otherwise specified, examples ofthe “alkylsulfonylamino (group)” include a C₁₋₆ alkylsulfonylamino(group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfonylamino (group)” include methylsulfonylamino,ethylsulfonylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₃₋₇ cycloalkylamino (group)” include cyclopropylamino,cyclopentylamino, cyclohexylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₇ cycloalkyl-carbonylamino (group)” includecyclopropylcarbonylamino, cyclopentylcarbonylamino,cyclohexylcarbonylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₈ cycloalkoxy-carbonylamino (group)” includecyclopropoxycarbonylamino, cyclopentyloxycarbonylamino,cyclohexyloxycarbonylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “C₃₋₈ cycloalkylsulfonylamino (group)” includecyclopropylsulfonylamino, cyclopentylsulfonylamino,cyclohexylsulfonylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₈₋₁₄ arylamino (group)” include phenylamino,diphenylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “mono- or di-C₇₋₁₆ aralkylamino (group)” include benzylamino and thelike.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryl-carbonylamino (group)” include benzoylamino,naphthoylamino and the like.

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ arylsulfonylamino (group)” include phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like.

[Substituent Group A]

(1) a halogen atom;

(2) nitro;

(3) cyano;

(4) an optionally esterified carboxy group;

(5) an optionally substituted alkyl group;

(6) an optionally substituted alkenyl group;

(7) an optionally substituted alkynyl group (e.g., an optionallysubstituted C₃₋₇ cycloalkyl-C₂₋₆ alkynyl group);

(8) an optionally substituted C₃₋₇ cycloalkyl group;

(9) an optionally substituted C₆₋₁₄ aryl group;

(10) an optionally substituted C₇₋₁₆ aralkyl group;

(11) an optionally substituted C₆₋₁₄ aryl-C₂₋₆ alkenyl group;

(12) an optionally substituted heterocyclic group;

(13) a hydroxy group;

(14) an optionally substituted alkoxy group;

(15) an optionally substituted C₃₋₇ cycloalkyloxy group;

(16) an optionally substituted C₆₋₁₄ aryloxy group;

(17) an optionally substituted C₇₋₁₆ aralkyloxy group;

(18) an optionally substituted alkyl-carbonyloxy group;

(19) an optionally substituted alkoxy-carbonyloxy group;

(20) an optionally substituted mono-alkyl-carbamoyloxy group;

(21) an optionally substituted di-alkyl-carbamoyloxy group;

(22) an optionally substituted C₆₋₁₄ aryl-carbonyloxy group;

(23) an optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyloxygroup;

(24) an optionally substituted heterocyclyl-oxy group (e.g., anoptionally substituted aromatic heterocyclyl-oxy group);

(25) an optionally substituted C₁₋₆ alkylsulfonyloxy group (e.g., anoptionally substituted halogeno C₁₋₆ alkylsulfonyloxy group);

(26) a mercapto group;

(27) an optionally substituted alkylsulfanyl group;

(28) an optionally substituted C₃₋₇ cycloalkylsulfanyl group;

(29) an optionally substituted C₆₋₁₄ arylsulfanyl group;

(30) an optionally, substituted C₇₋₁₆ aralkylsulfanyl group;

(31) an optionally substituted heterocyclyl-sulfanyl group;

(32) a formyl group;

(33) an optionally substituted alkyl-carbonyl group;

(34) an optionally substituted C₃₋₇ cycloalkyl-carbonyl group;

(35) an optionally substituted C₆₋₁₄ aryl-carbonyl group;

(36) an optionally substituted C₇₋₁₆ aralkyl-carbonyl group;

(37) an optionally substituted heterocyclyl-carbonyl group;

(38) an optionally substituted alkylsulfonyl group;

(39) an optionally substituted C₃₋₇ cycloalkylsulfonyl group;

(40) an optionally substituted C₆₋₁₄ arylsulfonyl group;

(41) an optionally substituted heterocyclyl-sulfonyl group;

(42) an optionally substituted alkylsulfinyl group;

(43) an optionally substituted C₃₋₇ cycloalkylsulfinyl group;

(44) an optionally substituted C₆₋₁₄ arylsulfinyl group;

(45) an optionally substituted heterocyclyl-sulfinyl group;

(46) a sulfo group;

(47) a sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) a thiocarbamoyl group;

(51) an optionally substituted carbamoyl group [e.g., an optionallysubstituted alkyl-carbamoyl and the like];

(52) an optionally substituted amino group

[e.g.,

amino,

an optionally substituted mono- or di-alkylamino group,

an optionally substituted mono- or di-C₃₋₇ cycloalkylamino group,

an optionally substituted mono- or di-C₆₋₁₄ arylamino group,

an optionally substituted mono- or di-C₇₋₁₆ aralkylamino group,

an optionally substituted heterocyclyl-amino group,

an optionally substituted C₆₋₁₄ aryl-carbonylamino group,

a formylamino group,

an optionally substituted alkyl-carbonylamino group (e.g., a mono-(C₁₋₆alkyl-carbonyl)-amino group),

an optionally substituted C₃₋₇ cycloalkyl-carbonylamino group,

an optionally substituted heterocyclyl-carbonylamino group,

an optionally substituted alkoxy-carbonylamino group,

an optionally substituted C₃₋₆ cycloalkoxy-carbonylamino group,

an optionally substituted heterocyclyl-oxycarbonylamino group,

an optionally substituted carbamoylamino group,

an optionally substituted alkylsulfonylamino group,

an optionally substituted C₃₋₈ cycloalkylsulfonylamino group,

an optionally substituted heterocyclyl-sulfonylamino group,

an optionally substituted C₆₋₁₄ arylsulfonylamino group];

(53) an optionally substituted alkoxy-carbonyl group;

(54) an optionally substituted C₆₋₁₄ aryloxy-carbonyl group;

(55) an optionally substituted C₇₋₁₆ aralkyloxy-carbonyl group.

The number of the substituents is preferably 0 (i.e., unsubstituted), or1 or 2.

The number of the substituents is more preferably 0 (i.e.,unsubstituted).

Among Substituent Group A, examples of the substituent of the“optionally substituted alkoxy-carbonyl group”,

“optionally substituted alkyl group”,

“optionally substituted alkenyl group”,

“optionally substituted alkynyl group”,

“optionally substituted alkoxy group”,

“optionally substituted alkyl-carbonyloxy group”,

“optionally substituted alkoxy-carbonyloxy group”,

“optionally substituted mono-alkyl-carbamoyloxy group”,

“optionally substituted di-alkyl-carbamoyloxy group”,

“optionally substituted C₁₋₆ alkylsulfonyloxy group”

“optionally substituted halogeno C₁₋₆ alkylsulfonyloxy group”,

“optionally substituted alkylsulfanyl group”,

“optionally substituted alkyl-carbonyl group”,

“optionally substituted alkylsulfonyl group”,

“optionally substituted alkylsulfinyl group”,

“optionally substituted alkyl-carbamoyl group”,

“optionally substituted mono- or di-alkylamino group”,

“optionally substituted alkyl-carbonylamino group”,

“optionally substituted mono-(C₁₋₆ alkyl-carbonyl)-amino group”,

“optionally substituted alkoxy-carbonylamino group” and

“optionally substituted alkylsulfonylamino group” include substituentsselected from the following Substituent Group B. The number of thesubstituents is 1 to the maximum substitutable number, more preferably 1to 3.

Among Substituent Group A, examples of the substituent of the“optionally substituted C₆₋₁₄ aryloxy-carbonyl group”,

“optionally substituted C₇₋₁₆ aralkyloxy-carbonyl group”,

“optionally substituted C₃₋₇ cycloalkyl-C₂₋₆ alkynyl group”,

“optionally substituted C₃₋₇ cycloalkyl group”,

“optionally substituted C₆₋₁₄ aryl group”,

“optionally substituted C₇₋₁₆ aralkyl group”,

“optionally substituted C₆₋₁₄ aryl-C₂₋₆ alkenyl group”,

“optionally substituted heterocyclic group”,

“optionally substituted C₃₋₇ cycloalkyloxy group”,

“optionally substituted C₆₋₁₄ aryloxy group”,

“optionally substituted C₇₋₁₆ aralkyloxy group”,

“optionally substituted C₆₋₁₄ aryl-carbonyloxy group”,

“optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyloxy group”,

“optionally substituted heterocyclyl-oxy group”,

“optionally substituted aromatic heterocyclyl-oxy group”,

“optionally substituted C₃₋₇ cycloalkylsulfanyl group”,

“optionally substituted C₆₋₁₄ arylsulfanyl group”,

“optionally substituted C₇₋₁₆ aralkylsulfanyl group”,

“optionally substituted heterocyclyl-sulfanyl group”,

“optionally substituted C₃₋₇ cycloalkyl-carbonyl group”,

“optionally substituted C₆₋₁₄ aryl-carbonyl group”,

“optionally substituted C₇₋₁₆ aralkyl-carbonyl group”,

“optionally substituted heterocyclyl-carbonyl group”,

“optionally substituted C₃₋₇ cycloalkylsulfonyl group”,

“optionally substituted C₆₋₁₄ arylsulfonyl group”,

“optionally substituted heterocyclyl-sulfonyl group”,

“optionally substituted C₃₋₇ cycloalkylsulfinyl group”,

“optionally substituted C₆₋₁₄ arylsulfinyl group”,

“optionally substituted heterocyclyl-sulfinyl group”,

“optionally substituted carbamoyl group”,

“optionally substituted amino group”,

“optionally substituted mono- or di-C₃₋₇ cycloalkylamino group”,

“optionally substituted mono- or di-C₆₋₁₄ arylamino group”,

“optionally substituted mono- or di-C₇₋₁₆ aralkylamino group”,

“optionally substituted heterocyclyl-amino group”,

“optionally substituted C₆₋₁₄ aryl-carbonylamino group”,

“optionally substituted C₃₋₈ cycloalkyl-carbonylamino group”,

“optionally substituted heterocyclyl-carbonylamino group”,

“optionally substituted C₃₋₈ cycloalkoxy-carbonylamino group”,

“optionally substituted heterocyclyl-oxycarbonylamino group”,

“optionally substituted carbamoylamino group”,

“optionally substituted C₃₋₈ cycloalkylsulfonylamino group”,

“optionally substituted heterocyclyl-sulfonylamino group” and

“optionally substituted C₆₋₁₄ arylsulfonylamino group” includesubstituents selected from the following Substituent Group B and thefollowing Substituent Group B′. The number of the substituents is 1 tothe maximum substitutable number, more preferably 1 to 3, further morepreferably 1.

In the present specification, Substituent Group B consists of

(a) a halogen atom;

(b) a hydroxy group;

(c) a nitro group;

(d) a cyano group;

(e) an optionally substituted C₆₋₁₄ aryl group (the C₆₋₁₄ aryl group isoptionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1)substituents selected from a halogen atom, hydroxy, cyano, amino,optionally halogenated C₁₋₆ alkyl by 1 to 3 halogen atoms, mono- ordi-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, mono- or di-C₇₋₁₆aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆ alkyl-carbonyl,C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl,C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl,C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamoyl,thiocarbamoyl, mono- or di-C₁₋₆ alkyl-carbamoyl, mono- or di-C₆₋₁₄aryl-carbamoyl and the like);(f) an optionally substituted C₆₋₁₄ aryloxy group (the C₆₋₁₄ aryloxygroup is optionally substituted by 1 to 5 (preferably 1 to 3, morepreferably 1) substituents selected from a halogen atom, hydroxy, cyano,amino, optionally halogenated C₁₋₆ alkyl by 1 to 3 halogen atoms, mono-or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, mono- or di-C₇₋₁₆aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆ alkyl-carbonyl,C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl,C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl,C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamoyl,thiocarbamoyl, mono- or di-C₁₋₆ alkyl-carbamoyl, mono- or di-C₆₋₁₄aryl-carbamoyl and the like);(g) an optionally substituted C₇₋₁₆ aralkyloxy group (the C₇₋₁₆aralkyloxy group is optionally substituted by 1 to 5 (preferably 1 to 3,more preferably 1) substituents selected from a halogen atom, hydroxy,cyano, amino, optionally halogenated C₁₋₆ alkyl by 1 to 3 halogen atoms,mono- or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, mono- ordi-C₇₋₁₆ aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆alkyl-carbonyl, C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C₁₋₆alkyl-carbamoyl, mono- or di-C₆₋₁₄ aryl-carbamoyl and the like);(h) an optionally substituted 5- to 10-membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom (e.g., furyl, pyridyl, thienyl, 1-pyrrolidinyl,1-piperidyl, 4-piperidyl, piperazinyl, 1-morpholinyl, 4-thiomorpholinyl,1-azepanyl, 1-azocanyl, 1-azonanyl, 3,4-dihydroisoquinolin-2-yl and thelike) (the heterocyclic group is optionally substituted by 1 to 5(preferably 1 to 3, more preferably 1) substituents selected m from ahalogen atom, hydroxy, cyano, amino, optionally halogenated C₁₋₆ alkylby 1 to 3 halogen atoms, mono- or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄arylamino, mono- or di-C₇₋₁₆ aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,formyl, C₁₋₆ alkyl-carbonyl, C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, C₁₋₆ alkylsulfanyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- ordi-C₁₋₆ alkyl-carbamoyl, mono- or di-C₆₋₁₄ aryl-carbamoyl and the like);(i) an optionally substituted amino group [e.g., an amino groupoptionally substituted by 1 or 2 substituent(s) selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₆₋₁₄ aryl, C₇₋₁₆ aralkyl, aheterocyclic group and heterocyclyl-alkyl (the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₆₋₁₄ aryl, C₇₋₁₆ aralkyl, heterocyclic group and heterocyclyl-alkyl areeach optionally substituted by 1 to 5 (preferably 1 to 3, morepreferably 1) substituents selected from a halogen atom, hydroxy, cyano,amino, C₁₋₆ alkyl optionally halogenated by 1 to 3 halogen atoms (whichis not a substituent for alkyl and alkenyl), mono- or di-C₁₋₆alkylamino, mono- or di-C₆₋₁₄ arylamino, mono- or di-C₇₋₁₆ aralkylamino,C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₃₋₇ cycloalkyloxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, C₁₋₆ alkylsulfanyl, C₃₋₇ cycloalkylsulfanyl,C₁₋₆ alkylsulfinyl, C₃₋₇ cycloalkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇cycloalkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C₁₋₆alkyl-carbamoyl, mono- or di-C₆₋₁₄ aryl-carbamoyl and the like).Examples of the “heterocyclic group” and the “heterocyclyl-” of the“heterocyclyl-alkyl” include those similar to the above-mentioned“heterocyclic group”];(j) C₃₋₇ cycloalkyl;(k) an optionally substituted C₁₋₆ alkoxy group (the C₁₋₆ alkoxy groupis optionally substituted by 1 to 5 (preferably 1 to 3, morepreferably 1) substituents selected from a halogen atom, hydroxy, amino,mono- or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, C₁₋₆alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamoyl,thiocarbamoyl, mono- or di-C₁₋₆ alkyl-carbamoyl, mono- or di-C₆₋₁₄aryl-carbamoyl, trimethylsilyl (TMS) and the like);(l) a formyl group;(m) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl);(n) a C₃₋₇ cycloalkyl-carbonyl group;(o) a C₆₋₁₄ aryl-carbonyl group;(p) a C₇₋₁₆ aralkyl-carbonyl group;(q) a C₁₋₆ alkoxy-carbonyl group;(r) a C₆₋₁₄ aryloxy-carbonyl group;(s) a C₇₋₁₆ aralkyloxy-carbonyl group;(t) a C₁₋₆ alkylsulfanyl group;(u) a C₁₋₆ alkylsulfinyl group;(v) a C₁₋₆ alkylsulfonyl group;(w) a carbamoyl group;(x) a thiocarbamoyl group;(y) a mono-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl and the like);(z) a di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl and the like);(aa) a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl,1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like);(bb) a mono- or di-(5- to 7-membered heterocyclyl containing 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom)-carbamoyl group (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and thelike); and(cc) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy and the like).

In the present specification, Substituent Group B′ consists of

(a) an optionally substituted C₁₋₆ alkyl group (the C₁₋₆ alkyl group isoptionally substituted by 1 to 5 (preferably 1 to 3, more preferably 1)substituents selected from a halogen atom, hydroxy, cyano, amino, mono-or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, mono- or di-C₇₋₁₆aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆ alkyl-carbonyl,C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl,C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl,C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamoyl,thiocarbamoyl, mono- or di-C₁₋₆ alkyl-carbamoyl, mono- or di-C₆₋₁₄aryl-carbamoyl and the like);(b) an optionally substituted C₂₋₆ alkenyl group (the C₂₋₆ alkenyl groupis optionally substituted by 1 to 5 (preferably 1 to 3, morepreferably 1) substituents selected from a halogen atom, hydroxy, cyano,amino, mono- or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, mono-or di-C₇₋₁₆ aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆alkyl-carbonyl, C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C₁₋₆alkyl-carbamoyl, mono- or di-C₆₋₁₄ aryl-carbamoyl and the like); and(c) an optionally substituted C₂₋₆ alkynyl group (the C₂₋₆ alkynyl groupis optionally substituted by 1 to 5 (preferably 1 to 3, morepreferably 1) substituents selected from a halogen atom, hydroxy, cyano,amino, mono- or di-C₁₋₆ alkylamino, mono- or di-C₆₋₁₄ arylamino, mono-or di-C₇₋₁₆ aralkylamino, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, formyl, C₁₋₆alkyl-carbonyl, C₃₋₇ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C₁₋₆alkyl-carbamoyl, mono- or di-C₆₋₁₄ aryl-carbamoyl and the like).

Each symbol in formula (I) is explained in the following.

Ring A is an optionally substituted 6-membered ring.

Any one or two of Z¹ to Z⁴, which are ring A-constituting atoms, is(are)—N═, and the others are —CH═. That is, the “6-membered ring” of the“optionally substituted 6-membered ring” for ring A is a pyridine ring,a pyridazine ring, a pyrimidine ring or a pyrazine ring, preferably apyridine ring or a pyrimidine ring.

Preferably, Z¹ or Z² is —N═ and the others are —CH═; or Z¹ and Z³ are—N═ and the others are —CH═.

More preferably, Z¹ is —N═ and the others (i.e., Z², Z³ and Z⁴) are—CH═; or Z¹ and Z³ are —N═ and the others (i.e., Z² and Z⁴) are —CH═.

Particularly preferably, Z¹ is —N═ and the others (i.e., Z², Z³ and Z⁴)are —CH═.

The nitrogen atom of —N═ for Z¹ to Z⁴ may be oxidized. For example, whenZ¹ is —N═ and the others (i.e., Z², Z³ and Z⁴) are each —CH═, a compoundrepresented by the formula:

wherein each symbol is as defined above, is also encompassed in thecompound represented by the formula (I). Particularly, when Z¹ is —N═,the nitrogen atom of —N═ for Z¹ is preferably oxidized.

Examples of the substituent of the “optionally substituted 6-memberedring” for ring A include substituents selected from the above-mentionedSubstituent Group A.

Among them, a halogen atom, cyano, an optionally substituted alkylgroup, an optionally substituted alkoxy group and the like arepreferable,

a halogen atom, cyano, an optionally substituted C₁₋₆ alkyl group and anoptionally substituted C₁₋₆ alkoxy group are more preferable,

a halogen atom (preferably a chlorine atom, a fluorine atom), cyano, aC₁₋₆ alkyl group (preferably methyl) optionally substituted by 1 to 3substituents selected from the group consisting of (1) a halogen atom(preferably a fluorine atom), (2) hydroxy and (3) a C₁₋₆alkyl-carbonyloxy group (preferably acetoxy), and a C₁₋₆ alkoxy group(preferably methoxy, ethoxy) optionally substituted by 1 to 3 halogenatoms (preferably a fluorine atom) are further more preferable, anda halogen atom (preferably a chlorine atom, a fluorine atom), cyano,methyl, hydroxymethyl, acetoxymethyl, trifluoromethyl, methoxy,difluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy areparticularly preferable.

The number of the substituents of the “optionally substituted 6-memberedring” for ring A is 0 (i.e., unsubstituted), or 1 to 3, preferably 0, or1 to 2, more preferably 0 or 1. When the number of the substituents isnot less than 2, the respective substituents may be the same ordifferent.

Ring A is preferably a pyridine ring or a pyrimidine ring, each of whichis optionally substituted by 1 to 3 substituents selected from a halogenatom, cyano, an optionally substituted alkyl group and an optionallysubstituted alkoxy group [preferably a halogen atom, cyano, anoptionally substituted C₁₋₆ alkyl group and an optionally substitutedC₁₋₆ alkoxy group, more preferably a halogen atom (preferably a chlorineatom, a fluorine atom), cyano, a C₁₋₆ alkyl group (preferably methyl)optionally substituted by 1 to 3 substituents selected from the groupconsisting of (1) a halogen atom (preferably a fluorine atom), (2)hydroxy, and (3) a C₁₋₆ alkyl-carbonyloxy group (preferably acetoxy),and a C₁₋₆ alkoxy group (preferably methoxy, ethoxy) optionallysubstituted by 1 to 3 halogen atoms (preferably a fluorine atom),further more preferably a halogen atom (preferably a chlorine atom, afluorine atom), cyano, methyl, trifluoromethyl, hydroxymethyl,acetoxymethyl, methoxy, difluoromethoxy, 2,2-difluoroethoxy and2,2,2-trifluoroethoxy, further more preferably a fluorine atom, methyl,hydroxymethyl and methoxy].

In another embodiment, ring A is preferably

(1) a pyridine ring which is optionally substituted by one substituentselected from (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from a halogen atom, hydroxy and a C₁₋₆alkyl-carbonyloxy group (preferably methyl, trifluoromethyl,acetoxymethyl, hydroroxymethyl), (ii) a halogen atom (preferablychlorine, fluorine), (iii) cyano, and (iv) a C₁₋₄ alkoxy groupoptionally substituted by 1 to 3 halogen atoms (preferably methoxy,difluoromethoxy, difluoroethoxy, trifluoroethoxy)[preferably a pyridine ring which is optionally substituted by (1) apyridine ring which is optionally substituted by one substituentselected from (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from a halogen atom and hydroxy (preferablymethyl, trifluoromethyl, hydroxymethyl), (ii) a halogen atom (preferablychlorine, fluorine), (iii) cyano, and (iv) a C₁₋₄ alkoxy optionallysubstituted by 1 to 3 halogen atoms (preferably methoxy,difluoromethoxy, difluoroethoxy, trifluoroethoxy)], or (2) a pyrimidinering.

Y is an oxygen atom, a sulfur atom, an optionally substituted methylenegroup or —NR^(c)—.

Examples of the substituent of the “optionally substituted methylenegroup” for Y include substituents selected from the above-mentionedSubstituent Group A.

Among them, an optionally substituted alkyl group and the like arepreferable.

The number of the substituents of the “optionally substituted methylenegroup” for Y is 0 (i.e., unsubstituted), 1 or 2. When the number of thesubstituents is 2, the respective substituents may be the same ordifferent.

The “alkyl group” of the “optionally substituted alkyl group”exemplified as the substituent of the “optionally substituted methylenegroup” for Y is preferably a C₁₋₆ alkyl group (preferably methyl) or thelike.

As the substituent of the “optionally substituted alkyl group”exemplified as the substituent of the “optionally substituted methylenegroup” for Y, a halogen atom, a hydroxy group, a C₃₋₇ cycloalkyl group,an optionally substituted C₁₋₆ alkoxy group (e.g., a trimethylsilyl-C₁₋₆alkoxy group), a C₁₋₆ alkoxy-carbonyl group and the like are preferable.

The number of the substituents of the “optionally substituted alkylgroup” exemplified as the substituent of the “optionally substitutedmethylene group” for Y is preferably 0 (i.e., unsubstituted), or 1 to 5,particularly preferably 0 (i.e., unsubstituted). When the number of thesubstituents is not less than 2, the respective substituents may be thesame or different.

When the number of the substituents of the “optionally substitutedmethylene group” for Y is 2, these two substituents optionally form,together with the adjacent carbon atom, an optionally substituted C₃₋₆cycloalkane (preferably cyclobutane).

As the substituent of the “optionally substituted C₃₋₆ cycloalkane”, ahalogen atom, a hydroxy group, a C₃₋₇ cycloalkyl group, an optionallysubstituted C₁₋₆ alkoxy group (e.g., a trimethylsilyl-C₁₋₆ alkoxygroup), a C₁₋₆ alkoxy-carbonyl group and the like are preferable.

The number of the substituents of the “optionally substituted C₃₋₆cycloalkane” is preferably 0 (i.e., unsubstituted), or 1 to 5,particularly preferably 0 (i.e., unsubstituted). When the number of thesubstituents is not less than 2, the respective substituents may be thesame or different.

R^(c) is a hydrogen atom or a substituent.

Examples of the substituent for R^(c) include substituents selected fromthe above-mentioned Substituent Group A.

Among them, an optionally substituted alkyl group, an optionallysubstituted C₃₋₇ cycloalkyl group and the like are preferable.

The “alkyl group” of the “optionally substituted alkyl group”exemplified as the substituent for R^(c) is preferably a C₁₋₆ alkylgroup (preferably methyl, ethyl, propyl, isopropyl, isobutyl) or thelike.

As the substituent of the “optionally substituted alkyl group”exemplified as the substituent for R^(c), a halogen atom (preferably afluorine atom), a hydroxy group, a C₃₋₇ cycloalkyl group (preferablycyclopropyl), an optionally substituted C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy, a trimethylsilyl-C₁₋₆ alkoxy group (preferablytrimethylsilyl-ethoxy)), a C₁₋₆ alkoxy-carbonyl group (preferablyethoxycarbonyl) and the like are preferable.

The number of the substituents of the “optionally substituted alkylgroup” exemplified as the substituent for R^(c) is preferably 0 (i.e.,unsubstituted), or 1 to 5, more preferably 0 (i.e., unsubstituted), or 1to 3. When the number of the substituents is not less than 2, therespective substituents may be the same or different.

The “optionally substituted C₃₋₇ cycloalkyl group” exemplified as thesubstituent for R^(e) is preferably cyclopropyl or the like.

As the substituent of the “optionally substituted C₃₋₇ cycloalkyl group”exemplified as the substituent for R^(e), a halogen atom, a hydroxygroup, a C₃₋₇ cycloalkyl group, an optionally substituted C₁₋₆ alkoxygroup (e.g., methoxy, ethoxy, a trimethylsilyl-C₁₋₆ alkoxy group), aC₁₋₆ alkoxy-carbonyl group and the like are preferable.

The number of the substituents of the “optionally substituted C₃₋₇cycloalkyl group” is preferably 0 (i.e., unsubstituted), or 1 to 5,particularly preferably 0 (i.e., unsubstituted). When the number of thesubstituents is not less than 2, the respective substituents may be thesame or different.

Y is preferably an oxygen atom, an optionally substituted methylenegroup, or —NR^(c)— wherein R^(e) is preferably a hydrogen atom, anoptionally substituted alkyl group or an optionally substituted C₃₋₇cycloalkyl group,

more preferably an oxygen atom, a methylene group optionally substitutedby 1 or 2 C₁₋₆ alkyl group(s) (preferably methyl) (the two substituentsfor the methylene group optionally form, together with the adjacentcarbon atom, a C₃₋₆ cycloalkane (preferably cyclobutane)), or —NR^(c)—wherein R^(c) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group(preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionallysubstituted by 1 to 3 (preferably 1 or 2) substituents selected from thegroup consisting of a halogen atom (preferably a fluorine atom), ahydroxy group, a C₃₋₇ cycloalkyl group (preferably cyclopropyl), anoptionally substituted C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, atrimethylsilyl-C₁₋₆ alkoxy group (preferably trimethylsilyl-ethoxy)) anda C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl), or (iii) aC₃₋₇ cycloalkyl group (preferably cyclopropyl),particularly preferably —NR^(c)— wherein R^(c) is preferably a C₁₋₆alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl), adiC₁₋₆ alkylmethylene group (preferably dimethylmethylene group) or thelike, more preferably —NR^(c)— wherein R^(c) is preferably a C₁₋₆ alkylgroup (preferably methyl, ethyl, isopropyl).

In another embodiment, Y is preferably —NR^(c)— wherein R^(c) ispreferably an optionally substituted C₁₋₆ alkyl group, more preferably aC₁₋₆ alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a halogen atom (preferably a fluorine atom), a hydroxygroup, a C₃₋₇ cycloalkyl group (preferably cyclopropyl), an optionallysubstituted C₁₋₆ alkoxy group (e.g., a trimethylsilyl-C₁₋₆ alkoxy group(preferably trimethylsilyl-ethoxy)) and a C₁₋₆ alkoxy-carbonyl group(preferably ethoxycarbonyl).

In another embodiment, Y is preferably —NR^(c)— wherein R^(c) ispreferably an optionally substituted C₁₋₆ alkyl group, more preferablyan optionally substituted C₁₋₄ alkyl group (preferably methyl, ethyl,propyl, isopropyl, isobutyl).

In another embodiment, Y is preferably a methylene group which isoptionally substituted by 1 to 2 C₁₋₆ alkyl group(s) (preferablymethyl), or —NR^(S)— wherein R^(c) is (1) a hydrogen atom, (2) a C₁₋₆alkyl which is optionally substituted by 1 to 3 substituents selectedfrom the group consisting of hydroxy and a halogen atom (preferablymethyl, ethyl, propyl, isopropyl, hydroxymethyl, difluoromethyl), or (3)a C₃₋₇ cycloalkyl (preferably cyclopropyl).

The partial structure of the formula (I):

is preferably, for example, a group represented by the formula:

-   -   wherein    -   Y¹ is an optionally substituted methylene group, or —NR^(c)—        wherein R^(c) is a hydrogen atom or a substituent, and ring A¹        is an optionally substituted pyridine ring, or        a group represented by the formula:

-   -   wherein    -   Y² is —NR^(d)— wherein R^(d) is a substituent, and ring A² is an        optionally substituted pyridine ring.

Examples of the “optionally substituted methylene group” for Y¹ includethose similar to the “optionally substituted methylene group” for Y.

Examples of the “substituent” of the “optionally substituted pyridinering” for ring A¹ include those similar to the “substituent” of the“optionally substituted 6-membered ring” for ring A.

Examples of the “substituent” for R^(d) include those similar to the“substituent” for 12′.

Among them, an optionally substituted alkyl group and the like arepreferably.

The “alkyl group” of the “optionally substituted alkyl group”exemplified as the substituent for R^(d) is preferably a C₁₋₆ alkylgroup (preferably a C₁₋₄ alkyl group, more preferably methyl, ethyl,propyl, isopropyl, isobutyl) or the like.

As the substituent of the “optionally substituted alkyl group”exemplified as the substituent for R^(d), a halogen atom (preferably afluorine atom), a hydroxy group, a C₃₋₇ cycloalkyl group (preferablycyclopropyl), an optionally substituted C₁₋₆ alkoxy group (e.g., atrimethylsilyl-C₁₋₆ alkoxy group (preferably trimethylsilyl-ethoxy)), aC₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl) and the like arepreferable, and a halogen atom (preferably a fluorine atom), a hydroxygroup, an optionally substituted C₁₋₆ alkoxy group (e.g., methoxy,ethoxy, a trimethylsilyl-C₁₋₆ alkoxy group (preferablytrimethylsilyl-ethoxy)), a C₁₋₆ alkoxy-carbonyl group (preferablyethoxycarbonyl) and the like are more preferable.

The number of the substituents of the “optionally substituted alkylgroup” exemplified as the substituent for R^(d) is preferably 0 (i.e.,unsubstituted), or 1 to 5, more preferably 0 (i.e., unsubstituted), or 1to 3. When the number of the substituents is not less than 2, therespective substituents may be the same or different.

Examples of the “substituent” of the “optionally substituted pyridinering” for ring A² include those similar to the “substituent” of the“optionally substituted 6-membered ring” for ring A.

The partial structure of the formula (I):

is more preferably a group represented by the formula:

wherein each symbol is as defined above, further more

-   -   preferably a group represented by the formula:

-   -   wherein    -   R³ is a hydrogen atom, a halogen atom, cyano, an optionally        substituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆        alkoxy group, and    -   Y¹ is as defined above.

The “optionally substituted C₁₋₆ alkyl group” for R³ is preferably anoptionally substituted C₁₋₄ alkyl group, more preferably a C₁₋₄ alkylgroup (preferably methyl) optionally substituted by 1 to 3 halogen atoms(preferably a fluorine atom).

The “optionally substituted C₁₋₆ alkoxy group” for R³ is preferably anoptionally substituted C₁₋₄ alkoxy group, more preferably a C₁₋₄ alkoxygroup (preferably methoxy, ethoxy) optionally substituted by 1 to 3halogen atoms (preferably a fluorine atom).

R³ is preferably a halogen atom (preferably a chlorine atom, a fluorineatom), cyano, C₁₋₆ alkyl (preferably C₁₋₄ alkyl, more preferably methyl)optionally substituted by 1 to 3 halogen atoms (preferably a fluorineatom), or C₁₋₆ alkoxy (preferably C₁₋₄ alkoxy, more preferably methoxy,ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably afluorine atom), particularly preferably a halogen atom (preferably achlorine atom, a fluorine atom), cyano, trifluoromethyl,difluoromethoxy, 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy.

In another embodiment, R³ is preferably a hydrogen atom, a halogen atom(preferably a chlorine atom, a fluorine atom), cyano, an optionallysubstituted C₁₋₄ alkyl group or an optionally substituted C₁₋₄ alkoxygroup, more preferably a hydrogen atom, a halogen atom (preferably achlorine atom, a fluorine atom), an optionally substituted C₁₋₄ alkylgroup or an optionally substituted C₁₋₄ alkoxy group.

The partial structure of the formula (I):

is particularly preferably a group represented by the formula:

-   -   wherein    -   R³′″ is a hydrogen atom, a halogen atom, an optionally        substituted C₁₋₆ alkyl group (preferably an optionally        substituted C₁₋₄ alkyl group) or an optionally substituted C₁₋₆        alkoxy group (preferably an optionally substituted C₁₋₄ alkoxy        group), and    -   Y¹ is as defined above.

In another embodiment, the group represented by the formula:

is preferably

-   -   wherein    -   R⁴′ is an optionally substituted C₁₋₆ alkyl group, and    -   R³ is as defined above.

The “optionally substituted C₁₋₆ alkyl group” for R⁴′ is preferably anoptionally substituted C₁₋₄ alkyl group, more preferably a C₁₋₄ alkylgroup (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofa halogen atom (preferably a fluorine atom), a hydroxy group, a C₃₋₇cycloalkyl group (preferably cyclopropyl), an optionally substitutedC₁₋₆ alkoxy group (preferably C₁₋₄ alkoxy) (e.g., methoxy, ethoxy, atrimethylsilyl-C₁₋₆ alkoxy group (preferably trimethylsilyl-ethoxy)),and a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl).

R⁴′ is preferably an optionally substituted C₁₋₆ alkyl group, morepreferably an optionally substituted C₁₋₄ alkyl group.

In another embodiment, the partial structure of the formula (I):

is preferably a group represented by the formula:

-   -   wherein    -   R³″″ and R³′″″ represent the same or different a hydrogen atom,        a halogen atom, cyano, an optionally substituted C₁₋₆ alkyl        group or an optionally substituted C₁₋₆ alkoxy group, and        R⁴′ is as defined above.

The “optionally substituted C₁₋₆ alkyl group” for R³″″ or R³′″″ ispreferably an optionally substituted C₁₋₄ alkyl group, more preferably aC₁₋₄ alkyl group (preferably methyl) optionally substituted by 1 to 3halogen atoms (preferably a fluorine atom).

The “optionally substituted C₁₋₆ alkoxy group” for R³″″ or R³′″″ ispreferably an optionally substituted C₁₋₄ alkoxy group, more preferablya C₁₋₄ alkoxy group (preferably methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (preferably a fluorine atom).

R³″″ is preferably a hydrogen atom, a halogen atom, an optionallysubstituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆ alkoxygroup, more preferably a hydrogen atom or an optionally substituted C₁₋₆alkyl group, further more preferably a hydrogen atom or an optionallysubstituted C₁₋₄ alkyl group (preferably methyl, hydroxymethly).

R³′″″ is preferably a hydrogen atom, a halogen atom, cyano, anoptionally substituted C₁₋₆ alkyl group or an optionally substitutedC₁₋₆ alkoxy group, more preferably a hydrogen atom, a halogen atom,cyano, an optionally substituted C₁₋₄ alkyl group or an optionallysubstituted C₁₋₄ alkoxy group.

The group represented by the formula:

is preferably a group represented by the formula:

-   -   wherein    -   R^(3a) and R^(3b) represent the same or different a hydrogen        atom, a halogen atom, cyano, an optionally substituted C₁₋₄        alkyl group or an optionally substituted C₁₋₄ alkoxy group, and    -   R⁴ represents an optionally substituted C₁₋₄ alkyl group,        provided that when one of R^(3a) and R^(3b) is a hydrogen atom,        the other is not a hydrogen atom, and        more preferably a group represented by the formula:

-   -   wherein    -   R³′ represents a hydrogen atom, or an optionally substituted        C₁₋₄ alkyl group (preferably, methyl, hydroxymethly),    -   R³″ represents a hydrogen atom, a halogen atom, cyano, an        optionally substituted C₁₋₄ alkyl group or an optionally        substituted C₁₋₄ alkoxy group, and    -   R⁴ represents an optionally substituted C₁₋₄ alkyl group,        provided that when one of R³′ and R³″ is a hydrogen atom, the        other is not a hydrogen atom.

R³″ is preferably a hydrogen atom, a halogen atom, an optionallysubstituted C₁₋₄ alkyl group (preferably, methyl) or an optionallysubstituted C₁₋₄ alkoxy group (preferably, methoxy).

R is

(1) a group represented by the formula:

or(2) a group represented by the formula:

That is, the compound represented by the formula (I) or a salt thereofencompasses a compound represented by the formula

(I-1) or the formula (I-2):

Each symbol for R is explained in the following.

wherein

-   -   R¹ is a phenyl group or a 5- to 10-membered heterocyclic group,        each of which is optionally substituted,    -   L is a sulfur atom (—S—), an oxygen atom (—O—), an optionally        substituted methylene group, —CO—, —NR^(a)—, —CH₂O—, —OCH₂—,        —NR^(a)COO—, —OCONR^(a)—, —NR^(a)CONR^(b)—, —NR^(a)COCH₂—,        —CH₂CONR^(a)—, —NR^(a)CO—, —CONR^(a)—,

-   -   -   wherein        -   R^(a) and R^(b) are the same or different and each is a            hydrogen atom or an optionally substituted C₁₋₆ alkyl group,            or

    -   L and R¹ in combination optionally form an optionally        substituted bi- or tri-cyclic fused heterocyclic group, and ring        B¹ is a benzene ring, a pyridine ring, a pyrimidine ring, a        pyrazine ring or a pyridazine ring, each of which is optionally        substituted.

Examples of the “5- to 10-membered heterocyclic group” of the“optionally substituted 5- to 10-membered heterocyclic group” for R¹include a 5- to 10-membered heterocyclic group from among the “3- to14-membered heterocyclic groups” exemplified above.

Among them, a 5- or 6-membered monocyclic heterocyclic group, a bicyclicfused heterocyclic group (preferably a 9- to 10-membered bicyclic fusedheterocyclic group) and the like are preferable.

The nitrogen atom(s) contained in the “5- to 10-membered heterocyclicgroup” of the “optionally substituted 5- to 10-membered heterocyclicgroup” for R¹ may be oxidized.

The “5- or 6-membered monocyclic heterocyclic group” is preferably, forexample, a 5- or 6-membered monocyclic nitrogen-containing aromaticheterocyclic group such as imidazolyl, pyridyl, pyridazinyl, pyrazinyl,pyrimidinyl, thiadiazolyl and the like. Among them, imidazolyl, pyridyland thiadiazolyl are preferable, and the following groups:

and the like are more preferable, and the following groups:

are particularly preferable.

Examples of the aforementioned “bicyclic fused heterocyclic group”include (1) a fused heterocyclic group formed by condensation of aphenyl group with a 5- or 6-membered heterocycle, (2) a fusedheterocyclic group formed by condensation of a 5- or 6-memberedheterocyclic group with a carbocycle having 5 or 6 carbon atoms, and (3)a fused heterocyclic group formed by condensation of a 5- or 6-memberedheterocyclic group with a 5- or 6-membered heterocycle. Among them, thefollowing groups:

-   -   wherein R^(f) is absent or a hydrogen atom (when R^(f) is        absent,    -   N(R^(f))— is ═N—; R^(f) is preferably absent),        and the like are preferable, and the following groups:

and the like are more preferable.

Examples of the substituent of the “phenyl group or 5- to 10-memberedheterocyclic group, each of which is optionally substituted” for R¹include substituents selected from the above-mentioned Substituent GroupA.

Among them,

(a) a halogen atom,

(b) an optionally esterified carboxy group,

(c) an optionally substituted alkyl group,

(d) an optionally substituted C₆₋₁₄ aryl group,

(e) an optionally substituted alkyl-carbonyl group,

and the like are preferable,

(a) a halogen atom (preferably fluorine, bromine, chlorine),

(b) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),

(c) a C₁₋₆ alkyl group (preferably methyl, ethyl, butyl, isobutyl)optionally substituted by one or more (preferably 1 to 3) substituentsselected from the group consisting of

-   -   (i) a halogen atom (preferably a fluorine atom),    -   (ii) a hydroxy group, and    -   (iii) an optionally substituted C₁₋₆ alkoxy group (e.g., a C₁₋₆        alkoxy group (preferably ethoxy) optionally substituted by        trimethylsilyl),        (d) a C₆₋₁₄ aryl group (preferably phenyl),        (e) a C₁₋₆ alkyl-carbonyl group (preferably acetyl), and the        like are more preferable.

The number of the substituents of the “phenyl group or 5- to 10-memberedheterocyclic group, each of which is optionally substituted” for R¹ ispreferably 0 (i.e., unsubstituted), or 1 to 3. When the number of thesubstituents is not less than 2, the respective substituents may be thesame or different.

R¹ is preferably a phenyl group, imidazolyl, pyridyl, thiadiazolyl(preferably the following group:

or the like, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of

-   -   (a) a halogen atom,    -   (b) an optionally esterified carboxy group,    -   (c) an optionally substituted alkyl group,    -   (d) an optionally substituted C₆₋₁₄ aryl group, and    -   (e) an optionally substituted alkyl-carbonyl group    -   [preferably    -   (a) a halogen atom (preferably fluorine, bromine, chlorine),    -   (b) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),    -   (c) a C₁₋₆ alkyl group (preferably methyl, ethyl, butyl,        isobutyl) optionally substituted by one or more (preferably 1        to 3) substituents selected from the group consisting of        -   (i) a halogen atom (preferably fluorine),        -   (ii) a hydroxy group, and        -   (iii) an optionally substituted C₁₋₆ alkoxy group (e.g., a            C₁₋₆ alkoxy group (preferably ethoxy) optionally substituted            by trimethylsilyl),    -   (d) a C₆₋₁₄ aryl group (preferably phenyl), and    -   (e) a C₁₋₆ alkyl-carbonyl group (preferably acetyl)].

In another embodiment, R¹ is preferably

-   -   wherein    -   R^(x) is a hydrogen atom or an optionally substituted C₁₋₆ alkyl        group (preferably a C₁₋₆ alkyl group),        or the like.

Examples of the substituent of the “optionally substituted methylenegroup” for L include substituents selected from the above-mentionedSubstituent Group A.

The “optionally substituted methylene group” for L is preferably(unsubstituted) methylene.

Preferable examples of the substituent of the “optionally substitutedC₁₋₆ alkyl group” for R^(a) include substituents selected from theabove-mentioned Substituent Group A.

R^(a) is preferably a hydrogen atom, a C₁₋₆ alkyl group or the like,more preferably a hydrogen atom, methyl or the like.

Preferable examples of the substituent of the “optionally substitutedC₁₋₆ alkyl group” for R^(b) include substituents selected from theabove-mentioned Substituent Group A.

R^(b) is preferably a hydrogen atom, a C₁₋₆ alkyl group or the like,more preferably a hydrogen atom, methyl or the like.

L is preferably an oxygen atom (—O—), —CO—, —NR^(a)—, —NR^(a)COO—wherein R^(a) is preferably a hydrogen atom or a C₁₋₆ alkyl group(preferably methyl), or

more preferably an oxygen atom or —NR^(a)— wherein R^(a) is a hydrogenatom or a C₁₋₆ alkyl group (preferably methyl), or the like,further more preferably an oxygen atom or the like.

The “optionally substituted bi- or tri-cyclic fused heterocyclic groupformed by L and R¹ in combination” means that the moiety represented bythe formula:

is a moiety represented by the formula:

-   -   wherein    -   R^(y) is an optionally substituted bi- or tri-cyclic fused        heterocyclic group, and    -   B¹ is as defined above.

That is, the substituent on the ring-constituting atom of the “phenylgroup” or the “5- to 10-membered heterocyclic group” for R¹ and thesubstituent on the main chain-constituting atom of L form a ringtogether with the ring-constituting atom and the main chain-constitutingatom. In the present specification, this structure is sometimesrepresented by the following formula:

Examples of the “bi- or tri-cyclic fused heterocyclic group” of the“optionally substituted bi- or tri-cyclic fused heterocyclic group”formed by L and R¹ in combination include a bi- or tri-cyclic group,from among the aforementioned “3- to 14-membered heterocyclic groupscontaining 1 to 5 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom”.

The “bi- or tri-cyclic fused heterocyclic group” is preferably thefollowing group:

-   -   wherein    -   X is —CH₂—, —NH—, an oxygen atom or a sulfur atom,    -   X′ is ═CH— or ═N—, and    -   R^(f) is absent or a hydrogen atom (when R^(f) is absent,        N(R^(f))— is ═N—; R^(f) is preferably absent),        or the like, more preferably the following group:

Examples of the substituent of the “optionally substituted bi- ortri-cyclic fused heterocyclic group” optionally formed by L and R¹ incombination include substituents selected from the aforementionedSubstituent Group A and an oxo group.

Among them,

(a) a halogen atom,

(b) an optionally esterified carboxy group,

(c) an optionally substituted alkyl group,

(d) an oxo group

and the like are preferable, and

(a) a halogen atom,

(b) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),

(c) a C₁₋₆ alkyl group (preferably methyl) optionally substituted byC₆₋₁₄ aryl group(s) (preferably phenyl),

(d) an oxo group

and the like are more preferable, and

(a) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),

(b) a C₁₋₆ alkyl group (preferably methyl) optionally substituted byC₆₋₁₄ aryl group(s) (preferably phenyl), and

(c) an oxo group

are further more preferable.

In another embodiment, as the substituents of the “optionallysubstituted bi- or tri-cyclic fused heterocyclic group” optionallyformed by L and R¹ in combination,

(a) a halogen atom,

(b) an optionally esterified carboxy group,

(c) an optionally substituted alkyl group,

and the like are preferable, and

(a) a halogen atom,

(b) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),

(c) a C₁₋₆ alkyl group (preferably methyl) optionally substituted byC₆₋₁₄ aryl group(s) (preferably phenyl),

and the like are more preferable, and

(a) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl), and

(b) a C₁₋₆ alkyl group (preferably methyl) optionally substituted byC₆₋₁₄ aryl group(s) (preferably phenyl) are further more preferable.

The number of the substituents of the “optionally substituted bi- ortri-cyclic fused heterocyclic group” optionally formed by L and R¹ incombination is preferably 0 (i.e., unsubstituted), or 1 to 3. When thenumber of the substituents is not less than 2, the respectivesubstituents may be the same or different.

The “optionally substituted bi- or tri-cyclic fused heterocyclic group”optionally formed by L and R¹ in combination is preferably

each of which is optionally substituted by 1 to 3 substituents selectedfrom the group consisting of

-   -   (a) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),    -   (b) C₁₋₆ alkyl group (preferably methyl) optionally substituted        by C₆₋₁₄ aryl group(s) (preferably phenyl), and    -   (c) an oxo group.

The partial structure of the formula (I-1):R¹-L—is preferably a group represented by the following formula:

-   -   wherein    -   R^(f) is absent or a hydrogen atom (when R^(f) is absent,        —N(R^(f))— is ═N—; R^(f) is preferably absent);    -   R^(z) is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group optionally        substituted by one substituent selected from (1) a hydroxy group        (preferably, methyl, ethyl, hydroxyethyl, buthyl,        hydroxyisobutyl) and (2) a C₁₋₄ alkoxy group optionally        substituted by trimethylsilyl (preferably,        trimethylsilylmethoxy), or (iii) a C₁₋₆ alkyl-carbonyl group        (preferably, acetyl);    -   R^(w1) is a halogen atom (preferably, fluorine);    -   m is 0 to 2;    -   R^(w2) is a hydrogen atom or a methyl group;    -   R^(w3) is a hydrogen atom or a C₁₋₂ alkoxy-carbonyl group        (preferably, ethoxycarbonyl);    -   R^(w4) is a hydrogen atom or benzyl;    -   R^(w5) is a hydrogen atom or methyl;    -   R^(w6) is a hydrogen atom, a halogen atom (preferably, fluorine,        chlorine), or a C₁₋₆ alkyl group optionally substituted by 1 to        3 halogen atoms (preferably, trifluoromethyl);    -   R^(w7) is a C₁₋₆ alkoxyl-carbonyl group (preferably,        ethoxycarbonyl);    -   R^(w8) is a halogen atom (preferably, chlorine, bromine), or a        C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms        (preferably, trifluoromethyl);    -   n is 0 to 2;    -   R^(w9) is a hydrogen atom or a halogen atom (preferably,        bromine);        more preferably a group represented by the following formula:

-   -   wherein        -   R^(w1) is a halogen atom (preferably, fluorine);    -   m is 0 to 1;    -   R^(z) is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group optionally        substituted by one hydroxy group (preferably, methyl,        hydroxyethyl, hydroxyisobutyl) and    -   R^(w3) is a hydrogen atom or a C₁₋₂ alkoxy-carbonyl group        (preferably, ethoxycarbonyl).

In another embodiment, the partial structure of the formula (I-1):R¹-L—is preferably a group represented by the following formula:

-   -   wherein    -   R^(x) is an optionally substituted C₁₋₆ alkyl group,        each of which is further optionally substituted.

The “optionally substituted C₁₋₆ alkyl group” for R^(x) is preferably aC₁₋₆ alkyl group (preferably methyl, ethyl, butyl, isobutyl) optionallysubstituted by one or more (preferably 1 to 3) substituents selectedfrom the group consisting of

-   -   (i) a halogen atom (preferably a fluorine atom),    -   (ii) a hydroxy group, and    -   (iii) an optionally substituted C₁₋₆ alkoxy group (e.g., a C₁₋₆        alkoxy group (preferably ethoxy) optionally substituted by        trimethylsilyl),        more preferably a C₁₋₆ alkyl group (preferably methyl, ethyl,        butyl, isobutyl) optionally substituted by one or more        (preferably 1 to 3) substituents selected from the group        consisting of    -   (i) a hydroxy group, and    -   (ii) an optionally substituted C₁₋₆ alkoxy group (e.g., a C₁₋₆        alkoxy group (preferably ethoxy) optionally substituted by        trimethylsilyl).

As the substituent that the group represented by the formula:

-   -   wherein    -   R″ is an optionally substituted C₁₋₆ alkyl group,        optionally further has,        (a) a halogen atom,        (b) an optionally esterified carboxy group,        (c) an optionally substituted alkyl group,        (d) an optionally substituted C₆₋₁₄ aryl group,        (e) an optionally substituted alkyl-carbonyl group,        and the like are preferable, and        (a) a halogen atom (preferably fluorine),        (b) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),        (c) a C₁₋₆ alkyl group (preferably methyl)        and the like are more preferable.

The number of the substituents is preferably 0 (i.e., unsubstituted), or1 to 3, more preferably 0 (i.e., unsubstituted), or 1. When the numberof the substituents is not less than 2, the respective substituents maybe the same or different.

The cyclic moiety of the group represented by the formula:

(i.e., the moiety other than the substituent) is preferably

or the like, more preferably

Examples of the substituent of the “benzene ring, pyridine ring,pyrimidine ring, pyrazine ring or pyridazine ring, each of which isoptionally substituted” for ring B¹ include substituents selected fromthe above-mentioned Substituent Group A.

Among them, a halogen atom, an optionally substituted alkyl group andthe like are preferable,

a halogen atom, an optionally substituted C₁₋₆ alkyl group and the likeare more preferably, and

a halogen atom (preferably a fluorine atom),

a C₁₋₆ alkyl group (preferably methyl) and the like are further morepreferable.

The number of the substituents of the “benzene ring, pyridine ring,pyrimidine ring, pyrazine ring or pyridazine ring, each of which isoptionally substituted” for ring B¹ is preferably 0 (i.e.,unsubstituted), or 1 to 3, more preferably 0 or 1. When the number ofthe substituents is not less than 2, the respective substituents may bethe same or different.

Ring B¹ is preferably an optionally substituted benzene ring, morepreferably a benzene ring optionally substituted by 1 to 3 substituentsselected from the group consisting of a halogen atom and an optionallysubstituted alkyl group. [more preferably a halogen atom and anoptionally substituted C₁₋₆ alkyl group, further more preferably ahalogen atom (preferably a fluorine atom) and a C₁₋₆ alkyl group(preferably methyl), particularly preferably a halogen atom (preferablya fluorine atom)].

The compound represented by the formula (I-1) or a salt thereof ispreferably a compound wherein

Z¹ is —N═ and the others (i.e., Z², Z³, and Z⁴) are —CH═; or Z¹ and Z³are —N═ and the others (i.e., Z² and Z⁴) are —CH═ [preferably Z¹ is —N═and the others (i.e., Z², Z³, and Z⁴) are —CH═];

ring A is a pyridine ring or a pyrimidine ring, each of which isoptionally substituted by 1 to 3 substituents selected from the groupconsisting of a halogen atom, cyano, an optionally substituted alkylgroup and an optionally substituted alkoxy group [preferably a halogenatom, cyano, an optionally substituted C₁₋₆ alkyl group and anoptionally substituted C₁₋₆ alkoxy group, further more preferably ahalogen atom (preferably a chlorine atom, a fluorine atom), cyano, aC₁₋₆ alkyl group (preferably methyl) optionally substituted by 1 to 3substituents selected from the group consisting of (1) a halogen atom(preferably a fluorine atom), (2) hydroxyl, and (3) C₁₋₆ alkyl-carbonylgroup (preferably acetoxy), and a C₁₋₆ alkoxy group (preferably methoxy,ethoxy) optionally substituted by 1 to 3 halogen atoms (preferably afluorine atom)];Y is an oxygen atom, an optionally substituted methylene group, or—NR^(c)— wherein R^(c) is preferably a hydrogen atom, an optionallysubstituted alkyl group or an optionally substituted C₃₋₇ cycloalkylgroup{preferablyan oxygen atom,a methylene group optionally substituted by 1 or 2 C₁₋₆ alkyl groups(preferably methyl) (the two substituents for the methylene groupoptionally form, together with the adjacent carbon atom, a C₃₋₆cycloalkane (preferably cyclobutane)), or —NR^(c)— wherein R^(c) ispreferably (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group (e.g., methyl,ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3substituents selected from the group consisting of a halogen atom(preferably a fluorine atom), a hydroxy group, a C₃₋₇ cycloalkyl group(preferably cyclopropyl), an optionally substituted C₁₋₆ alkoxy group(e.g., methoxy, ethoxy, a trimethylsilyl-C₁₋₆ alkoxy group (preferablytrimethylsilyl-ethoxy)), and an C₁₋₆ alkoxy-carbonyl group (preferablyethoxycarbonyl), or (iii) a C₃₋₇ cycloalkyl group (preferablycyclopropyl)};R¹ is a phenyl group or a 5- to 10-membered heterocyclic group[preferably imidazolyl, pyridyl, thiadiazolyl (preferably the followinggroup:

each of which is optionally substituted by 1 to 3 substituents selectedfrom the group consisting of

-   -   (a) a halogen atom,    -   (b) an optionally esterified carboxy group,    -   (c) an optionally substituted alkyl group,    -   (d) an optionally substituted C₆₋₁₄ aryl group, and    -   (e) an optionally substituted alkyl-carbonyl group    -   [preferably    -   (a) a halogen atom (preferably fluorine, bromine, chlorine),    -   (b) a C₁₋₆ alkoxy-carbonyl group (preferably ethoxycarbonyl),    -   (c) a C₁₋₆ alkyl group (preferably methyl, ethyl, butyl,        isobutyl) optionally substituted by one or more (preferably 1        to 3) substituents selected from the group consisting of        -   (i) a halogen atom (preferably fluorine),        -   (ii) a hydroxy group, and        -   (iii) an optionally substituted C₁₋₆ alkoxy group (e.g., a            C₁₋₆ alkoxy group (preferably ethoxy) optionally substituted            by trimethylsilyl),    -   (d) a C₆₋₁₄ aryl group (preferably phenyl), and    -   (e) a C₁₋₆ alkyl-carbonyl group (preferably acetyl)];        L is an oxygen atom (—O—), —CO—, —NR^(a)—, —NR^(a)COO— wherein        R^(a) is preferably a hydrogen atom or a C₁₋₆ alkyl group        (preferably methyl), or

[preferably an oxygen atom, or —NR^(a)— wherein R^(a) is a hydrogen atomor a C₁₋₆ alkyl group (preferably methyl)); orL and R¹ in combination optionally form a bi- or tri-cyclic fusedheterocyclic group optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a C₁₋₆ alkoxy-carbonyl group(preferably ethoxycarbonyl),

-   -   (b) a C₁₋₆ alkyl group (preferably methyl) optionally        substituted by C₆₋₁₄ aryl group(s) (preferably phenyl), and    -   (c) an oxo group        (preferably

andring B¹ is preferably an optionally substituted benzene ring, morepreferably a benzene ring optionally substituted by 1 to 3 substituentsselected from the group consisting of a halogen atom and an optionallysubstituted alkyl group [preferably a halogen atom and an optionallysubstituted C₁₋₆ alkyl group, more preferably a halogen atom (preferablya fluorine atom) and a C₁₋₆ alkyl group (preferably methyl)],or a salt thereof.

In another embodiment, the compound represented by the formula (I-1) ora salt thereof is preferably a compound wherein

Z¹ is —N═,

Z², Z³ and Z⁴ are —CH═,

Y is —NR^(c)— or a di-C₁₋₆ alkylmethylene group,

R^(c) is a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, a C₃₋₇ cycloalkyl group, a trimethylsilyl-C₁₋₆ alkoxygroup and a C₁₋₆ alkoxy-carbonyl group, R¹ is a 5- to 10-memberedheterocyclic group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom,    -   (b) a C₁₋₆ alkoxy-carbonyl group,    -   (c) a C₁₋₆ alkyl group optionally substituted by one or more        (preferably 1 to 3) substituents selected from the group        consisting of        -   (i) a hydroxy group, and        -   (ii) an optionally substituted C₁₋₆ alkoxy group (e.g., a            C₁₋₆ alkoxy group optionally substituted by trimethylsilyl),            and    -   (d) a C₁₋₆ alkyl-carbonyl group;        L is an oxygen atom, or —NR^(a)— wherein R^(a) is a hydrogen        atom or a C₁₋₆ alkyl group, or        L and R¹ in combination optionally form a bi- or tri-cyclic        fused heterocyclic group optionally substituted by 1 to 3        substituents selected from the group consisting of    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by C₆₋₁₄ aryl        group(s), and    -   (c) an oxo group, and        ring B¹ is a benzene ring,        or a salt thereof.

The compound represented by the formula (I-1) or a salt thereof is morepreferably a compound wherein

Z¹ is —N═,

Z², Z³ and Z⁴ are —CH═,

Y is —NR^(c)— wherein R^(c) is a C₁₋₆ alkyl group, or a di-C₁₋₆alkylmethylene group,

R¹ is

wherein R^(x) is a hydrogen atom or a C₁₋₆ alkyl group,

L is an oxygen atom, and

ring B¹ is a benzene ring,

or a salt thereof.

In the partial structure of the formula (I-2):

R² is a phenyl group or a 5- to 10-membered heterocyclic group, each ofwhich is optionally substituted,ring B² is a benzene ring, a pyridine ring, a pyrimidine ring, apyrazine ring or a pyridazine ring, each of which is optionallysubstituted, andring D is an optionally further substituted 5- or 6-membered ring.

Examples of the “5- to 10-membered heterocyclic group” of the “phenylgroup or 5- to 10-membered heterocyclic group, each of which isoptionally substituted” for R² include those similar to the “5- to10-membered heterocyclic group” of the “optionally substituted 5- to10-membered heterocyclic group” for R¹.

Among them, a 5- or 6-membered monocyclic heterocyclic group, a bicyclicfused heterocyclic group (preferably a 9- or 10-membered bicyclic fusedheterocyclic group) and the like are preferable.

The “5- or 6-membered monocyclic heterocyclic group” is preferably, forexample, a 5- or 6-membered monocyclic nitrogen-containing aromaticheterocyclic group such as imidazolyl, pyridyl, pyridazinyl, pyrazinyl,pyrimidinyl, thiazolyl and the like, (preferably pyridyl, pyrimidinyl,thiazolyl etc.). Among them, the following group:

and the like are preferable, and the following group:

are more preferable.

Examples of the aforementioned “bicyclic fused heterocyclic group”include (1) a fused heterocyclic group formed by condensation of aphenyl group with a 5- or 6-membered heterocycle, (2) a fusedheterocyclic group formed by condensation of a 5- or 6-memberedheterocyclic group with a benzene ring, and (3) a fused heterocyclicgroup formed by condensation of a 5- or 6-membered heterocyclic groupwith a 5- or 6-membered heterocycle. Among them, the following group:

and the like are preferable, and the following group:

are more preferable.

Examples of the substituent of the “phenyl group or 5- to 10-memberedheterocyclic group, each of which is optionally substituted” for R²include substituents selected from the above-mentioned Substituent GroupA.

Among them, an optionally substituted alkyl group and the like arepreferable, a C₁₋₆ alkyl group and the like are more preferable, andmethyl is further more preferable.

The number of the substituents of the “phenyl group or 5- to 10-memberedheterocyclic group, each of which is optionally substituted” for R² ispreferably 0 (i.e., unsubstituted), or 1 to 3, more preferably 0 or 1.When the number of the substituents is not less than 2, the respectivesubstituents may be the same or different.

R² is preferably a 5- to 10-membered heterocyclic group (preferably thefollowing group:

more preferably the following group:

further more preferably the following group:

optionally substituted by 1 to 3 (preferably 1) substituents selectedfrom an optionally substituted alkyl group (preferably a C₁₋₆ alkylgroup, more preferably methyl).

Examples of the substituent of the “benzene ring, pyridine ring,pyrimidine ring, pyrazine ring or pyridazine ring, each of which isoptionally substituted” for ring B² include substituents selected fromthe above-mentioned Substituent Group A.

The number of the substituents is preferably 0 (i.e., unsubstituted), or1 to 3, more preferably 0. When the number of the substituents is notless than 2, the respective substituents may be the same or different.

Ring B² is preferably an optionally substituted benzene ring, morepreferably a benzene ring.

The “5- or 6-membered ring” of the “optionally further substituted 5- or6-membered ring” for ring D is a carbocycle having 5 or 6 carbon atoms(e.g., benzene) or a 5- or 6-membered heterocycle (e.g., pyrrolidine,dihydropyrrole, dihydropyrazole).

Among them, a pyrrolidine ring, a dihydropyrrole ring and adihydropyrazole ring are preferable, and a pyrrolidine ring is morepreferable.

Examples of the substituent of the “optionally further substituted 5- or6-membered ring” for ring D include substituents selected from theabove-mentioned Substituent Group A.

Among them, an optionally substituted alkyl group and the like arepreferable, a C₁₋₆ alkyl group and the like are more preferable, andmethyl is further more preferable.

The number of the substituents of the “optionally further substituted 5-or 6-membered ring” for ring D is preferably 0 (i.e., unsubstituted), or1 to 3, more preferably 0 or 1, more preferably 0. When the number ofthe substituents is not less than 2, the respective substituents may bethe same or different.

Ring D is preferably a pyrrolidine ring, a dihydropyrrole ring or adihydropyrazole ring, each of which is optionally substituted, morepreferably a pyrrolidine ring, a dihydropyrrole ring or adihydropyrazole ring.

The partial structure of the formula (I-2):

is preferably a structure represented by the formula:

wherein each symbol is as defined above.

The partial structure of the formula (I-2):

is preferably

-   -   wherein    -   R^(x1) and R^(x2) are the same or different and each is a        hydrogen atom or an optionally substituted C₁₋₆ alkyl group,    -   R^(x3)-R^(x5) are each a hydrogen atom or an optionally        substituted C₁₋₆ alkyl group, and    -   the ring-constituting atom(s) optionally further have        substituent(s),        and the like, more preferably

-   -   wherein the ring-constituting atom(s) optionally further have        substituent(s),        further more preferably

particularly preferably

Examples of the “optionally substituted C₁₋₆ alkyl group” for R^(x1) orR^(x2) include those similar to the “optionally substituted C₁₋₆ alkylgroup” exemplified as the substituent for ring D.

Examples of the “optionally substituted C₁₋₆ alkyl group” forR^(x3)-R^(x5) include those similar to the “optionally substituted C₁₋₆alkyl group” exemplified as the substituent for ring D.

Examples of the substituent that the aforementioned ring-constitutingatom(s) optionally further have include those similar to exemplified asthe substituent for ring B² or ring D.

The compound represented by the formula (I-2) or a salt thereof ispreferably a compound wherein

Z¹ is —N═ and the others (i.e., Z², Z³ and Z⁴) are —CH═; or Z¹ and Z³are —N═ and the others (i.e., Z² and Z⁴) are —CH═ [preferably Z¹ is —N═and the others (i.e., Z², Z³ and Z⁴) are —CH═];

ring A is a pyridine ring or a pyrimidine ring, each of which isoptionally substituted by 1 to 3 substituents selected from the groupconsisting of a halogen atom, cyano, an optionally substituted alkylgroup and an optionally substituted alkoxy group [preferably a halogenatom, cyano, optionally substituted C₁₋₆ alkyl and optionallysubstituted C₁₋₆ alkoxy, more preferably a halogen atom (preferably achlorine atom, a fluorine atom), cyano, C₁₋₆ alkyl (preferably methyl)optionally substituted by 1 to 3 halogen atoms (preferably a fluorineatom), and C₁₋₆ alkoxy (preferably methoxy, ethoxy) optionallysubstituted by 1 to 3 halogen atoms (preferably a fluorine atom)];Y is an oxygen atom, an optionally substituted methylene group, or—NR^(c)— wherein R^(c) is preferably a hydrogen atom, an optionallysubstituted alkyl group or an optionally substituted C₃₋₇ cycloalkylgroup{preferably an oxygen atom, a methylene group optionally substituted by1 or 2 C₁₋₆ alkyl group(s) (preferably methyl) (the two substituents forthe methylene group optionally form, together with the adjacent carbonatom, a C₃₋₆ cycloalkane (preferably cyclobutane)), or —NR^(c)— whereinR^(c) is preferably (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group(preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofa halogen atom (preferably a fluorine atom), a hydroxy group, a C₃₋₇cycloalkyl group (preferably cyclopropyl), an optionally substitutedC₁₋₆ alkoxy group (e.g., a trimethylsilyl-C₁₋₆ alkoxy group (preferablytrimethylsilyl-ethoxy)), and a C₁₋₆ alkoxy-carbonyl group (preferablyethoxycarbonyl), or (iii) a C₃₋₇ cycloalkyl group (preferablycyclopropyl)};R² is a 5- to 10-membered heterocyclic group (preferably the followinggroup:

optionally substituted by 1 to 3 (preferably 1) substituents selectedfrom an optionally substituted alkyl group (preferably a C₁₋₆ alkylgroup, more preferably methyl);ring B² is an optionally substituted benzene ring (preferably a benzenering); andring D is a pyrrolidine ring, a dihydropyrrole ring or a dihydropyrazolering, each of which is optionally substituted (preferably a pyrrolidinering, a dihydropyrrole ring or a dihydropyrazole ring),or a salt thereof.

The compound represented by the formula (I) or a salt thereof ispreferably a compound (W-1) wherein

Z¹ is —N═ and the others (i.e., Z², Z³ and Z⁴) are —CH═; or Z¹ and Z³are —N═ and the other (i.e., Z² and Z⁴) are —CH═;

wherein the nitrogen atom of —N═ for Z¹ may be oxidized; ring A is

(1) a pyridine ring which is optionally substituted by one substituentselected from (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from a halogen atom, hydroxy and a C₁₋₆alkyl-carbonyloxy (preferably methyl, trifluoromethyl, acetoxymethyl,hydroroxymethyl), (ii) a halogen atom (preferably chlorine, fluorine),(iii) cyano, and (iv) a C₁₋₄ alkoxy optionally substituted by 1 to 3halogen atoms (preferably methoxy, difluoromethoxy, difluoroethoxy,trifluoroethoxy), or(2) a pyrimidine ring,Y is a oxygen atom, a methylene group which is optionally substituted by1 to 2 C₁₋₆ alkyl group(s) (preferably methyl) (the two substituents forthe methylene group optionally form, together with the adjacent carbonatom, a C₃₋₆ cycloalkane (preferably cyclobutane)), or wherein R^(c) is(1) a hydrogen atom, (2) a C₁₋₆ alkyl group which is optionallysubstituted by 1 to 3 (preferably 1 or 2) substituents selected from thegroup consisting of (i) a C₁₋₆ alkoxy group optionally substituted bytrimethylsilyl, and (ii) a halogen atom (preferably methyl, ethyl,propyl, isopropyl, trimethylsilyl-ethoxy-methyl, difluoromethyl), or (3)a C₃₋₇ cycloalkyl (preferably cyclopropyl),R is(1) a group represented by the formula:

-   -   wherein    -   the partial structure:        R¹-L—    -   is a group represented by the following formula:

-   -   wherein

R^(f) is absent or a hydrogen atom (when R^(f) is absent,

N(R^(f))—is ═N—; R^(f) is preferably absent);

-   -   R^(z) is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group optionally        substituted by one substituent selected from (1) a hydroxy group        (preferably methyl, ethyl, hydroxyethyl, buthyl,        hydroxyisobutyl) and (2) a C₁₋₄ alkoxy group optionally        substituted by trimethylsilyl (preferably        trimethylsilylmethoxy), or (iii) a C₁₋₆ alkyl-carbonyl group        (preferably acetyl);    -   R^(w1) is a halogen atom (preferably fluorine);    -   m is 0 to 2;    -   R^(w2) is a hydrogen atom or a methyl group;    -   R^(w3) is a hydrogen atom or a C₁₋₂ alkoxy-carbonyl group        (preferably ethoxycarbonyl);    -   R^(w4) is a hydrogen atom or benzyl;    -   R^(w5) is a hydrogen atom or methyl;    -   R^(w6) is a hydrogen atom, a halogen atom (preferably fluorine,        chlorine), or a C₁₋₆ alkyl group optionally substituted by 1 to        3 halogen atoms (preferably trifluoromethyl);    -   R^(w7) is a C₁₋₆ alkoxyl-carbonyl group (preferably        ethoxycarbonyl);    -   R^(w8) is a halogen atom (preferably chlorine, bromine), or a        C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms        (preferably trifluoromethyl);    -   n is 0 to 2; and    -   R^(w9) is a hydrogen atom or a halogen atom (preferably        bromine); and    -   ring B¹ is a benzene ring optionally substituted by one halogen        atom (preferably fluorine); or        (2) a group represented by the formula:

-   -   wherein    -   R² is a 5- to 10-membered heterocyclic group (preferably the        following group:

-   -   optionally substituted by one C₁₋₆ alkyl group (preferably        methyl);    -   ring B² is a benzene ring; and    -   ring D is a pyrrolidine ring, a dihydropyrrole ring, a        dihydropirazole ring, (i.e., the partial structure of the        formula:

-   -   is

or a salt thereof.

In another embodiment, the compound represented by the formula (I) or asalt thereof is preferably a compound (W-2) wherein

Z¹ is —N═ and the others (i.e., Z², Z³ and Z⁴) are —CH═; or Z¹ and Z³are —N═ and the other (i.e., Z² and Z⁴) are —CH═; ring A is

(1) a pyridine ring which is optionally substituted by one substituentselected from (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from a halogen atom or hydroxy (preferably methyl,trifluoromethyl, hydroxymethyl), (ii) a halogen atom (preferablychlorine, fluorine), (iii) cyano, and (iv) a C₁₋₄ alkoxy optionallysubstituted by 1 to 3 halogen atoms (preferably methoxy,difluoromethoxy, difluoroethoxy, trifluoroethoxy), or(2) a pyrimidine ring,Y is a methylene group which is optionally substituted by 1 to 2 C₁₋₆alkyl group(s) (preferably methyl), or —NR^(c)— wherein 12′ is (1) ahydrogen atom, (2) a C₁₋₆ alkyl which is optionally substituted by 1 to3 substituents selected from the group consisting of hydroxy and ahalogen atom (preferably methyl, ethyl, propyl, isopropyl,hydroxymethyl, difluoromethyl), or(3) a C₃₋₇ cycloalkyl (preferably cyclopropyl),R is(1) a group represented by the formula:

-   -   wherein    -   the partial structure:        R¹-L—    -   is a group represented by the following formula:

-   -   -   wherein        -   R^(w1) is a halogen atom (preferably fluorine);        -   m is 0 to 1;        -   R^(z) is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group            optionally substituted by one hydroxy (preferably methyl,            hydroxyethyl, hydroxyisobutyl); and        -   R^(w3) is a hydrogen atom or a C₁₋₂ alkoxy-carbonyl group            (preferably, ethoxycarbonyl), and

    -   ring B¹ is a benzene ring; or        (2) a group represented by the formula:

-   -   wherein    -   R² is a 5- to 10-membered heterocyclic group (preferably the is        following group:

-   -   optionally substituted by one C₁₋₆ alkyl group (preferably        methyl); and    -   the partial structure of the formula:

-   -   is

or a salt thereof.

In another embodiment, the compound represented by the formula (I) or asalt thereof is preferably a compound represented by the formula:

-   -   wherein    -   R³′ is a hydrogen atom, or a C₁₋₆ alkyl which may optionally be        substituted by one hydroxy (i.e., methyl, hydroxymethyl);    -   R³″ is a hydrogen atom, a halogen atom (preferably fluorine), a        C₁₋₆ alkyl group (preferably methyl) or a C₁₋₆ alkoxy group        (preferably methoxy);    -   R⁴ is a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl);        or a salt thereof.

In another embodiment, the compound represented by the formula (I) or asalt thereof is preferably a compound wherein Z¹ is —N═ and the others(i.e., Z², Z³ and Z⁴) are —CH═;

ring A is a pyridine ring optionally substituted by a halogen atom,cyano, an optionally substituted alkyl group or an optionallysubstituted alkoxy group [preferably a halogen atom, cyano, optionallysubstituted C₁₋₆ alkyl or optionally substituted C₁₋₆ alkoxy, morepreferably a halogen atom (preferably a chlorine atom, a fluorine atom),cyano, C₁₋₆ alkyl (preferably methyl) optionally substituted by 1 to 3halogen atoms (preferably a fluorine atom), or C₁₋₆ alkoxy (preferablymethoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms(preferably a fluorine atom)];Y is —NR^(c)— wherein R^(c) is preferably an optionally substitutedalkyl group, more preferably a C₁₋₆ alkyl group (preferably methyl,ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3substituents selected from the group consisting of a halogen atom(preferably a fluorine atom), a hydroxy group, a C₃₋₇ cycloalkyl group(preferably cyclopropyl), an optionally substituted C₁₋₆ alkoxy group(e.g., a trimethylsilyl-C₁₋₆ alkoxy group (preferablytrimethylsilyl-ethoxy)) and a C₁₋₆ alkoxy-carbonyl group (preferablyethoxycarbonyl)]; andR is(1) a group represented by the formula:

-   -   wherein    -   the partial structure:        R¹-L—    -   is a group represented by the following formula:

-   -   -   wherein        -   R^(x) is an optionally substituted C₁₋₆ alkyl group            [preferably a C₁₋₆ alkyl group (preferably methyl, ethyl,            butyl, isobutyl) optionally substituted by 1 to 3            substituents selected from the group consisting of (i) a            hydroxy group and (ii) an optionally substituted C₁₋₆ alkoxy            group (e.g., a C₁₋₆ alkoxy group (preferably ethoxy)            optionally substituted by trimethylsilyl)]; and

    -   ring B¹ is an optionally substituted benzene ring [preferably a        benzene ring optionally substituted by 1 to 3 substituents        selected from the group consisting of a halogen atom and an        optionally substituted alkyl group (preferably a halogen atom        and an optionally substituted C₁₋₆ alkyl group, more preferably        a halogen atom (preferably a fluorine atom) and a C₁₋₆ alkyl        group (preferably methyl))], or        (2) a group represented by the formula:

-   -   wherein,    -   R² is a 5- to 10-membered heterocyclic group (preferably the        following group:

-   -   optionally substituted by 1 to 3 (preferably 1) substituents        selected from an optionally substituted alkyl group (preferably        a C₁₋₆ alkyl group, more preferably methyl);    -   ring B² is an optionally substituted benzene ring (preferably a        benzene ring); and    -   ring D is a pyrrolidine ring, a pyrrole ring or a pyrazole ring,        each of which is optionally substituted (preferably a        pyrrolidine ring, a pyrrole ring or a pyrazole ring),        or a salt thereof.

In another embodiment, the compound represented by the formula (I) or asalt thereof is preferably a compound wherein Z¹ is —N═ and the others(i.e., Z², Z³ and Z⁴) are —CH═; or Z¹ and Z³ are —N═ and the others(i.e., Z² and Z⁴) are —CH═; or Z¹ and Z⁴ are —N═ and the others (i.e.,Z² and Z³) are —CH═;

ring A is a pyridine ring, a pyrimidine ring or a pyrazine ring, each ofwhich is optionally substituted by 1 or 2 (preferably 1) substituentsselected from a halogen atom, an optionally substituted C₁₋₆ alkyl group(preferably a C₁₋₂ alkyl group such as methyl, ethyl and the like) andan optionally substituted C₁₋₆ alkoxy (e.g., methoxy) [preferably ahalogen atom (preferably a fluorine atom) and a methyl group];Y is —NR^(c)— wherein R^(c) is preferably a C₁₋₃ alkyl group (e.g.,methyl, ethyl, isopropyl), preferably —N(—CH₂CH₃)—; andR is a group represented by the formula:

-   -   wherein    -   the partial structure:        R¹-L—    -   is a group represented by the following formula:

-   -   -   wherein        -   R^(x) is an optionally substituted C₁₋₆ alkyl group            [preferably a C₁₋₆ alkyl group (preferably methyl, ethyl,            butyl, isobutyl) optionally substituted by 1 to 3            substituents selected from the group consisting of (i) a            hydroxy group and (ii) an optionally substituted C₁₋₆ alkoxy            group (e.g., methoxy)]; and

    -   ring B¹ is an optionally substituted benzene ring [preferably a        benzene ring optionally substituted by one substituent selected        from the group consisting of a halogen to atom and an optionally        substituted C₁₋₆ alkyl group, more preferably a halogen atom        (preferably a fluorine atom) and a C₁₋₆ alkyl group (preferably        methyl)] or a pyridine ring [more preferably a benzene ring],        or a salt thereof.

Among the embodiments of the above-mentioned formula (I), a compoundwherein ring A is a pyridine ring wherein Z¹ is —N═ and the others(i.e., Z², Z³ and Z⁴) are —CH═, and each of —CH═ for Z³ and Z⁴ has onesubstituent instead of a hydrogen atom, or the one of —CH═ for Z³ and Z⁴has one substituent instead of a hydrogen atom, is preferable, and acompound wherein ring A is a pyridine ring wherein Z¹ is —N═ and theothers (i.e., Z², Z³ and Z⁴) are —CH═, and —CH═ for Z⁴ has onesubstituent instead of a hydrogen atom, is more preferable. Examples ofthe substituent include a halogen atom, an optionally substituted C₁₋₆alkyl group (preferably a C₁₋₂ alkyl group such as methyl, ethyl and thelike) and an optionally substituted C₁₋₆ alkoxy (e.g., methoxy)[preferable examples thereof include a halogen atom (preferably afluorine atom) and a methyl group].

In another embodiment, the compound represented by the formula (I) or asalt thereof is preferably a compound represented by the formula (I′) ora salt thereof.

As the compound represented by the formula (I) or a salt thereof,

-   1-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof;-   1-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof;-   1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof;-   6-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof;-   1-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof;-   1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof; and-   1-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,    or a salt thereof    are preferable.

When the compound (I) is a salt, for example, metal salts, ammoniumsalts, salts with organic bases, salts with inorganic acids, salts withorganic acids, salts with basic or acidic amino acids can be included.Preferable examples of metal salts, for example, include alkali metalsalts such as sodium salts, potassium salts and the like; alkali earthmetal salts such as calcium salts, magnesium salts, barium salts and thelike; aluminum salts and the like. Preferable examples of salts withorganic bases include salts with trimethylamine, triethylamine,pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferable examples of saltswith inorganic acids include salts with hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid and the like.Preferable examples of salts with organic acids include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferable examples of salts withbasic amino acids include salts with arginine, lysine, ornithine and thelike. Preferable examples of salts with acidic amino acids include saltswith aspartic acid, glutamic acid and the like. Among them, salts thatare pharmacologically acceptable are preferable. For example, in thecase when acidic functional group are present in the compound, forexample, inorganic salts including alkali metal salts (e.g., sodiumsalts, potassium salts etc.), alkali earth metal salts (e.g., calciumsalts, magnesium salts, barium salts etc.) and the like, ammonium saltsand the like are preferable. In contrast, in the case when basicfunctional group are present in the compound, for example, salts withinorganic acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid etc. or salts with organic acidsuch as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid etc. are preferable.

In the following, compound (I) and a salt thereof are generally alsoreferred to as the compound of the present invention.

The compound (I) can be obtained in the crystal form. Either singlecrystalline form or crystalline mixture can be included in the compound(I).

The compound of the formula (I) can be a pharmaceutically acceptableco-crystal or a co-crystal salt. The term “co-crystal” or “co-crystalsalt” as used herein means a crystalline material composed of two ormore unique solids at room temperature, each of which has distinctivephysical characteristics such as structure, melting point, and heats offusion, hygroscopicity, solubility, and stability. A co-crystal or aco-crystal salt can be obtained according to a per se knownco-crystallization method.

The compound (I) can be provided as a solvate (e.g., hydrate) or as anon-solvate and both are included in the compound (I).

The compounds labeled with isotopes (e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S,¹²⁵I etc.) are also included in the compound (I).

Compound (I) labeled or substituted with an isotope can be utilized as,for example, a tracer (PET tracer) used for Positron Emission Tomography(PET) and is useful in the fields of medical diagnosis and the like.

[Manufacturing Method]

The methods for manufacturing compound (I), and compound (Ia), compound(Ia′) and compound (Ib) encompassed in compound (I) are explained in thefollowing.

whereinL¹ in compound (Ia) is a sulfur atom, an oxygen atom, an optionallysubstituted methylene group, —CO—, —NR^(a)—, —CH₂O—, —OCH₂—,—NR^(a)COO—, —OCONR^(a)—, —NR^(a)CONR^(b)—, —NR^(a)COCH₂—,—CH₂CONR^(a)—, —NR^(a)CO—, —CONR^(a)—,

the “optionally substituted methylene group” for L¹ means the same asthe “optionally substituted methylene group” for L, L² in compound (Ia′)forms, together with R¹, an optionally substituted bi- or tri-cyclicfused heterocyclic group, the “optionally substituted bi- or tri-cyclicfused heterocyclic group” formed by L² and R¹ in combination means thesame as the “optionally substituted bi- or tri-cyclic fused heterocyclicgroup” optionally formed by L and R¹, and other symbols are each asdefined above.

Compound (I) comprises compounds (Ia), (Ia′) and (Ib).

The compound of the present invention and starting compounds thereforcan be produced by a means known per se, for example, according to themethods shown by the following schemes and the like. In the following,the “room temperature” generally means 0-30° C., and each symbol in thechemical structural formulas described in the schemes is, unlessotherwise specified, as defined above. The compounds in the formulasalso include the salts formed, and examples of such salts include thosesimilar to the salts of compound (I) and the like. The compoundsobtained in respective steps can be used for the next reaction in theform of a reaction mixture or as a crude product. They can also beisolated from a reaction mixture according to a conventional method, andcan be easily purified by a separation means such as recrystallization,distillation, chromatography and the like. When the compounds in theformulas are commercially available, the commercially available productscan be directly used. In addition, when each ring in the formula (I) hasa substituent, the corresponding precursor has the same substituent.

When the starting compound contains an amino group, a carboxy group, ahydroxy group or a heterocyclic group, these groups may be protectedwith a protective group generally used in the peptide chemistry and thelike. In this case, after the reaction, the target compound can beobtained by removing the protective group as necessary. The protectivegroup can be introduced or removed by a method known per se, forexample, the method described in “Protective Groups in OrganicSynthesis, 3^(rd) Ed.” by Theodora W. Greene, Peter G. M. Wuts,Wiley-Interscience Corporation (1999) and the like. In the formula,P¹-P³ are each a nitrogen-protective group of an amino group or an amidegroup, a hydroxy-protective group, a carboxy-protective group, or ahydrogen atom, and those known per se can be used.

Examples of the nitrogen-protective group of an amino group or an amidegroup include a formyl group, and a C₁₋₆ alkyl-carbonyl group (e.g.,acetyl, ethylcarbonyl etc.), a phenylcarbonyl group, a C₁₋₆alkyl-oxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl(Boc) etc.), an allyloxycarbonyl(Alloc) group, aphenyloxycarbonyl group, a fluorenylmethoxycarbonyl(Fmoc) group, a C₇₋₁₀aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a C₇₋₁₀aralkyl-oxycarbonyl group (e.g., benzyloxycarbonyl(Z) etc.), a C₇₋₁₀aralkyl group (e.g., benzyl etc.), a 2-(trimethylsilyl)ethoxymethyl(SEM)group, a trityl group, a phthaloyl group, an N,N-dimethylaminomethylenegroup, a tert-butylcarbamate group, a benzylcarbamate group and thelike, each of which may have substituent(s). Examples of the substituentthese may have include a phenyl group, a halogen atom (e.g., fluorine,chlorine, bromine, iodine etc.), a C₁₋₆ alkyl-carbonyl group (e.g.,methylcarbonyl, ethylcarbonyl, butylcarbonyl etc.), a nitro group andthe like. The number of the substituents is about 1 to 3.

Examples of the carboxy-protective group include a C₁₋₆ alkyl group(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc.), anallyl group, a benzyl group, a phenyl group, a trityl group, a tri C₁₋₆alkylsilyl group and the like, each of which may have substituent(s).Examples of the substituents these may have include a halogen atom(e.g., fluorine, chlorine, bromine, iodine etc.), a formyl group, a C₁₋₆alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl, butylcarbonyl etc.),a nitro group and the like. The number of the substituents is about 1 to3.

Examples of the hydroxy-protective group include a C₁₋₆ alkyl group(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc.), aC₇₋₁₀ aralkyl group (e.g., benzyl etc.), a formyl group, a C₁₋₆alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl etc.), a benzoylgroup, a C₇₋₁₀ aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), atetrahydropyranyl group, a furyl group, a silyl group and the like, eachof which may have substituent(s). Examples of the substituent these mayhave include a halogen atom (e.g., fluorine, chlorine, bromine, iodineetc.), a C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl etc.), a phenylgroup, a C₇₋₁₀ aralkyl group (e.g., benzyl etc.), a C₁₋₆ alkoxy group(e.g., methoxy, ethoxy, n-propoxy etc.), a nitro group and the like. Thenumber of the substituents is about 1 to 4.

Preferable examples of P¹-P³ include a tert-butylcarbamate group, abenzylcarbamate group, a benzyl group, a C₁₋₆ alkyl group (e.g., amethyl group, an ethyl group) and the like. In addition, P¹-P³themselves can sometimes be the substituent of the compound of thepresent invention and, for example, a tert-butylcarbamate group, abenzylcarbamate group, a benzyl group, a C₁₋₆ alkyl group (e.g., amethyl group, an ethyl group) and the like can be mentioned.

As the “leaving group” for X¹-X¹², a halogen atom (e.g., a chlorineatom, a bromine atom, an iodine atom etc.), optionally halogenated C₁₋₆alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy,trifluoromethanesulfonyloxy, trifluoroethanesulfonyloxy etc.), C₆₋₁₀arylsulfonyloxy optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., benzenesulfonyloxy, p-toluenesulfonyloxy etc.), optionallyhalogenated C₁₋₆ alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl,trifluoroethanesulfonyl etc.) and the like are used. In addition, X¹-X¹²also include a substituent convertible to a leaving group, and thesubstituent can be converted to a leaving group by a reaction known perse in a desired step. For example, X¹-X¹² may be a methylthio groupconvertible to a methanesulfonyl group by an oxidation reaction.

When compound (I) contains optical isomer, stereoisomer, regioisomer,rotamer or tautomer, they are also encompassed in compound (I), and eachcan be obtained as a single isomer by a synthetic method and separationmethod known per se. For example, when compound (I) is an opticallyactive form, the racemate can be separated into (+) form and (−) form bya conventional optical resolution method.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method etc. described in detail below.

1) Fractional Recrystallization Method

A method wherein a salt of a racemate with an optically active compound(e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, aneutralization step to give a free optical isomer.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column forseparation of an optical isomer (a chiral column) to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series (manufactured byDaicel Chemical Industries, Ltd.) and the like, and developed withwater, various buffers (e.g., phosphate buffer, etc.) and organicsolvents (e.g., ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine etc.) solely or in admixture toseparate the optical isomer. In the case of a gas chromatography, forexample, a chiral column such as CP-Chirasil-DeX CB (manufactured by GLSciences Inc.) and the like is used to allow separation.

3) Diastereomer Method

A method wherein a racemate is prepared into a diastereomeric mixture bychemical reaction with an optically active reagent, which is made into asingle substance by a typical separation means (e.g., a fractionalrecrystallization method, a chromatography method etc.) and the like,and is subjected to a chemical treatment such as hydrolysis and the liketo separate an optically active reagent moiety, whereby an opticalisomer is obtained. For example, when compound (I) contains hydroxy, orprimary or secondary amino group within a molecule, the compound and anoptically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid etc.) and the like are subjected to condensation reaction to givediastereomers of the ester compound or the amide compound, respectively.When compound (I) has a carboxy group, this compound and an opticallyactive amine or an optically active alcohol reagent are subjected tocondensation reaction to give diastereomers of the amide compound or theester compound, respectively. The separated diastereomer is converted toan optical isomer of the original compound by acid hydrolysis or basehydrolysis.

Each step described below can be performed without solvent, or bydissolving or suspending in an appropriate solvent, where two or morekinds of solvents may be used by mixing them at an appropriate ratio. Ofthose recited as examples of the solvent to be used in the manufacturingmethod of the compound of the present invention, the following solventsare specifically used.

alcohols:

methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,2-methoxyethanol, 1-pentanol, etc.

ethers:

diethyl ether, diisopropyl ether, diphenylether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc. aromatic hydrocarbons:

benzene, chlorobenzene, toluene, xylene, etc.

saturated hydrocarbons:

cyclohexane, hexane, etc.

amides:

N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, N-methylpyrrolidone, etc.

halogenated hydrocarbons:

dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc.

nitriles:

acetonitrile, propionitrile, etc.

sulfoxides:

dimethylsulfoxide, etc.

aromatic organic bases:

pyridine, lutidine, etc.

esters:

methyl acetate, ethyl acetate, butyl acetate, etc.

Of those recited as examples of the base or deoxidizer to be used in themanufacturing method of the compound of the present invention, thefollowing bases and deoxidizers are specifically used.

inorganic bases:

sodium hydroxide, potassium hydroxide, magnesium hydroxide, etc.

basic salts:

sodium carbonate, potassium carbonate, cesium carbonate, calciumcarbonate, sodium hydrogen carbonate, etc.

organic bases:

triethylamine, diisopropylethylamine, tributylamine,cyclohexyldimethylamine, N¹,N²-dimethylethane-1,2-diamine, pyridine,lutidine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, etc.metal alkoxides:sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.alkali metal hydrides:sodium hydride, potassium hydride, etc.metal amides:sodium amide, lithiumdiisopropylamide, lithiumhexamethyl disilazide,etc.

Compound (Ia) can be produced by scheme 1. In addition, of compounds(Ia), the following compound (Ia-I) and compound (Ia-II) can also beproduced by scheme 2.

Compound (Ia′) can be produced by scheme 3. In addition, of compounds(Ia′), the following compound (Ia′-I) and compound (Ia′-II) can also beproduced by scheme 4, and the following compound (Ia′-III) can also beproduced by scheme 5.

Compound (Ib) can be produced by scheme 6. In addition, of compounds(Ib), the following compound (Ib-I) can also be produced by scheme 7.

Compound (Ia-III) can be produced by scheme 8.

In the formulas shown in these schemes 1-8, when the starting compoundin each reaction has a hydroxy group, an amino group and the like, thesegroups may be appropriately subjected to a general protection anddeprotection reactions (e.g., the reaction described in step 2). Theprotective groups may be selected, introduced or removed according to amethod known per se, for example, the method described in “ProtectiveGroups in Organic Synthesis, 3rd Ed.”, by Theodora W. Greene, Peter G.M. Wuts, Wiley-Interscience Corporation (1999), or a method analogousthereto and the like. In addition, when the starting compound in eachreaction has an amino group, a compound introduced with a nitro groupinstead of an amino group may be used as a starting compound, and afterthe reaction, the nitro group may be reduced to give a m desired aminogroup (e.g., the reaction described in step 7).

In addition, compound (I) can also be produced by an appropriatecombination of the reaction of each step shown by these schemes 1-8.

wherein X¹-X³ are each a leaving group, and the other symbols are asdefined above.

The compound of the present invention can be produced by subjectingcompound (IIa) to a series of reaction steps of Steps 1, 2, 3, 2′ and 6.

In addition, the compound can also be produced by subjecting compound(IIa) to a series of reaction steps in Steps 4, 2′ and 6.

Furthermore, the compound can also be produced by subjecting compound(IIf) to a series of reaction steps in Steps 5, 2′ and 6.

(Step 1)

Compound (IIc) can be produced by subjecting compound (IIa) and compound(IIb) to a substitution reaction. Compound (IIa) is generally used inabout 0.2-5.0 mol, preferably about 0.5-2.0 mol, per 1 mol of compound(IIb). This reaction is advantageously performed in a solvent inert tothe reaction. Such solvent is not particularly limited as long as thereaction proceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides, aromatic organic bases and the like or a mixedsolvent thereof and the like are preferable. In addition, when an acidicsubstance is released by the reaction, the reaction can be performed inthe presence of a deoxidizer to remove the acidic substance from thereaction system. As such deoxidizer, for example, inorganic bases, basicsalts, organic bases, metal alkoxides, alkali metal hydrides, metalamides and the like are used. The deoxidizer is generally used in about0.05-20 mol, preferably about 1-10 mol, per 1 mol of compound (IIb).While the reaction time varies depending on the reagent and solvent tobe used, it is generally 10 min-72 hr, preferably 30 min-24 hr. Thereaction temperature is generally 0-200° C., preferably 50-150° C. Inaddition, microwave irradiation may be performed to promote thereaction.

(Step 2)

Compound (IId) can be produced by removing the protective group (P²) ofcompound (IIc). When P² is a hydrogen atom, this step can be omitted.The protective group can be removed according to a method known per se,for example, the method described in “Protective Groups in OrganicSynthesis, 3rd Ed.” by Theodora W. Greene, Peter G. M. Wuts,Wiley-Interscience Corporation (1999), and the like. This reaction isadvantageously performed in a solvent inert to the reaction. Suchsolvent is not particularly limited as long as the reaction proceedsand, for example, solvents such as alcohols, ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides, aromatic organic bases and the like or a mixedsolvent thereof and the like are preferable. While the reaction timevaries depending on the reagent and solvent to be used, it is generally10 min-72 hr, preferably 30 min-24 hr. The reaction temperature isgenerally 0-200° C., preferably 0-50° C. In addition, microwaveirradiation may be performed to promote the reaction.

(Step 3)

Compound (IIe) can be produced by subjecting compound (IId) to acyclization reaction. The reaction can be performed according to amanufacturing method known per se or a method analogous thereto and, forexample, a method using a carbonating agent can be mentioned. Examplesof the carbonating agent include 1,1′-carbonylbis(1H-imidazole),phosgene, triphosgene, diethyl carbonate, dimethyl carbonate,di-tert-butyl dicarbonate and the like. When these carbonating agentsare used, the reaction is considered to proceed via a reactivederivative of amine. The synthesis from compound (IId) to compound (IIe)sometimes proceeds via compound (IIc). The carbonating agent isgenerally used in about 0.2-5.0 mol, preferably about 0.5-2.0 mol, per 1mol of compound (IId). In addition, a base can be used to promote thereaction. Examples of the base include inorganic bases, organic bases,metal alkoxides, alkali metal hydrides, metal amides and the like. Thebase is used in about 1.0-20 mol, preferably about 1.0-5.0 mol, per 1mol of compound (IId). This reaction is advantageously performed in asolvent inert to the reaction. Such solvent is not particularly limitedas long as the reaction proceeds and, for example, solvents such asethers, aromatic hydrocarbons, saturated hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic basesand the like or a mixed solvent thereof and the like are preferable.While the reaction time varies depending on the reagent and solvent tobe used, it is generally 10 min-72 hr, preferably 30 min-24 hr. Thereaction temperature is generally 0-200° C., preferably 0-100° C. Inaddition, microwave irradiation may be performed to promote thereaction.

(Step 4)

Compound (IIe) can also be produced by subjecting compound (IIa) andcompound (IIb) to a condensation reaction. This reaction can also beperformed according to a manufacturing method known per se, for example,the method described in Synlett, vol. 13, page 2083 (2006) and the like,or a method analogous thereto. Compound (IIa) is generally used in about0.2-5.0 mol, preferably about 0.5-2.0 mol, per 1 mol of compound (IIb).This reaction is advantageously performed in a solvent inert to thereaction. Such solvent is not particularly limited as long as thereaction proceeds and, for example, solvents such as alcohols, ethers,aromatic hydrocarbons, saturated hydrocarbons, amides, halogenatedhydrocarbons, nitriles, sulfoxides, aromatic organic bases and the likeor a mixed solvent thereof and the like are preferable. In addition,when an acidic substance is released from the reaction, the reaction canbe performed in the presence of a deoxidizer to remove the substancefrom the reaction system. As such deoxidizer, inorganic bases, basicsalts, organic bases, metal alkoxides, alkali metal hydrides, metalamides and the like are used. The deoxidizer is generally used in about0.05-20 mol, preferably about 1-10 mol, per 1 mol of compound (IIb). Inaddition, for example, basic salts, organic bases and the like can alsobe used to promote the reaction. Such basic salts, organic bases and thelike are generally used in about 0.05-20 mol, preferably about 1-10 mol,per 1 mol of compound (IIb). While the reaction time varies depending onthe reagent and solvent to be used, it is generally 10 min-200 hr,preferably 30 min-48 hr. The reaction temperature is generally 0-200°C., preferably 50-150° C. In addition, microwave irradiation may beperformed to promote the reaction.

(Step 5)

Compound (IIe) can be produced by subjecting compound (IIf) and compound(IIg) to a substitution reaction, or a coupling reaction in the presenceof a metal catalyst. Compound (IIg) is used in about 0.5-20 mol,preferably about 0.8-10 mol, per 1 mol of compound (IIf). As the metalcatalyst, a metal complex having a variety of ligands is used and, forexample, palladium compounds [e.g., palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,dichlorobis(triethylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II)acetate and 1,1′-bis(diphenylphosphino)ferrocene, complex of[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(DavePhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(Xphos),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)(Xantphos), ordicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane (SPhos), etc.],nickel compounds [e.g., tetrakis(triphenylphosphine)nickel (O),bis(triethylphosphine)nickel (II) chloride,bis(triphenylphosphine)nickel (II) chloride, etc.], copper compounds[e.g., copper oxide, copper(I) iodide, copper sulfate, copper(II)chloride, etc.] and the like can be mentioned. The metal catalyst isused in about 0.0001-5 mol, preferably about 0.001-1 mol, per 1 mol ofcompound (IIf). This reaction is preferably performed in the presence ofa base. Examples of the base include inorganic bases, organic bases,metal alkoxides, alkali metal hydrides, metal amides and the like. Thebase is used in about 1.0-20 mol, preferably about 1.0-5.0 mol, per 1mol of compound (IIf). To promote the reaction, for example, sodiumiodide, potassium iodide and the like may be added. Such sodium iodide,potassium iodide and the like are used in about 0.05-100 mol, preferablyabout 0.1-50 mol, per 1 mol of compound (IIf). In addition, when a metalcatalyst unstable to oxygen is used in this reaction, for example, thereaction is preferably performed in an inert gas stream such as argongas, nitrogen gas and the like. This reaction is advantageouslyperformed in a solvent inert to the reaction. Such solvent is notparticularly limited as long as the reaction proceeds and, for example,solvents such as alcohols, ethers, aromatic hydrocarbons, saturatedhydrocarbons, amides, nitriles, sulfoxides, esters, water and the likeor a mixed solvent thereof and the like are preferable. While thereaction time varies depending on the reagent and solvent to be used, itis generally 10 min-100 hr, preferably 30 min-50 hr. The reactiontemperature is −10 to 250° C., preferably 50 to 150° C. In addition,microwave irradiation may be performed to promote the reaction.

(Step 2′)

Compound (IIh) can be produced by removing the protective group (P¹) ofcompound (IIe). When P¹ is a hydrogen atom, this step can be omitted.This reaction may be performed according to a method similar to that ofthe above-mentioned (Step 2).

(Step 6)

Compound (Ia), which is the compound of the present invention, can beproduced by subjecting compound (IIh) and R¹—X³ to a substitutionreaction in the presence of a base. R¹—X³ is used in about 0.05-100 mol,preferably about 0.1-10 mol, per 1 mol of compound (IIh). Examples ofthe base include inorganic bases, basic salts, organic bases, metalamides, alkali metal hydrides and the like. The base is used in about0.5-10.0 mol, preferably about 1.0-5.0 mol, per 1 mol of compound (IIh).To promote the reaction, for example, sodium iodide, potassium iodideand the like may be added. Such sodium iodide, potassium iodide and thelike are used in about 0.05-100 mol, preferably about 0.1-50 mol, per 1mol of compound (IIh). This reaction is advantageously performed in asolvent inert to the reaction. The solvent is not particularly limitedas long as the reaction proceeds and, for example, solvents such asethers, aromatic hydrocarbons, saturated hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides and the like or a mixedsolvent thereof and the like are preferable. While the reaction timevaries depending on the reagent and solvent to be used, it is generally10 min-100 hr, preferably 30 min-24 hr. The reaction temperature isgenerally −20-250° C., preferably 0-230° C. In addition, microwaveirradiation may be performed to promote the reaction.

Compounds (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and (IIh) andR¹—X³ may be commercially available products, or can be producedaccording to a method known per se or a method analogous thereto. Inaddition, compound (IIa) can be produced according to the methoddescribed in Synlett, vol. 13, page 2083 (2006) and the like, or amethod analogous thereto. Compound (IIf) can also be produced accordingto the method described in Tetrahedron Letters, vol. 47, page 7567(1993), Journal of Medicinal Chemistry, vol. 10, page 2697 (1990) andthe like, or a method analogous thereto. Compound (IIh) and R¹—X³ canalso be produced by a known substituent conversion reaction,condensation reaction, oxidation reaction, reduction reaction and thelike, which may be used alone or in a combination of two or morethereof. These reactions may be performed, for example, according to themethod described in Shinjikken Kagaku Koza (Courses in ExperimentalChemistry), vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANICFUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC.,(1989); Comprehensive Organic Transformations, VCH Publishers Inc.(1989) and the like.

wherein X⁴ is a leaving group, and other symbols are as defined above.

Compound (Ia-I) and compound (Ia-II), which are the compounds of thepresent invention, can be produced by subjecting compound (IIIa) to aseries of reaction steps in Steps 1′, 7 and 3′, and Steps 1′, 7, 3′ and8, respectively.

(Step 1′)

Compound (IIIb) can be produced by reacting compound (IIIa) withcompound (IIa′). Compound (IIIa) is generally used in about 0.2-5.0 mol,preferably about 0.5-2.0 mol, per 1 mol of compound (IIa′). Thisreaction is advantageously performed in a solvent inert to the reaction.The solvent is not particularly limited as long as the reaction proceedsand, for example, solvents such as ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides, aromatic organic bases and the like or a mixed solventthereof and the like are preferable. In addition, when an acidicsubstance is released by the reaction, the reaction can be performed inthe presence of a deoxidizer to remove the substance from the reactionsystem. As the deoxidizer, for example, inorganic bases, basic salts,organic bases, metal alkoxides, alkali metal hydrides, metal amides andthe like are used. The deoxidizer is generally used in about 0.05-20mol, preferably about 0.1-10 mol, per 1 mol of compound (IIa′). Inaddition, for example, basic salts, organic bases and the like can alsobe used to promote the reaction. Such basic salts, organic bases and thelike are generally used in about 0.05-20 mol, preferably about 0.1-10mol, per 1 mol of compound (IIa′). While the reaction time variesdepending on the reagent and solvent to be used, it is generally 10min-72 hr, preferably 30 min-24 hr. The reaction temperature isgenerally 0-200° C., preferably 50-150° C. In addition, microwaveirradiation may be performed to promote the reaction.

(Step 7)

Compound (IIIc) can be produced by subjecting compound (IIIb) to areduction reaction. This reaction can be performed according to a methodknown per se such as the method described in Shinjikken Kagaku Koza(Courses in Experimental Chemistry), vols. 14 and 15 (The ChemicalSociety of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2ndedition, ACADEMIC PRESS, INC. (1989); Comprehensive OrganicTransformations, VCH Publishers Inc. (1989) and the like, or a methodanalogous thereto. For example, a method using a reducing agent can bementioned. Examples of the reducing agent include zinc, tin chloride,and complexes of hydrogen and, for example, palladium-carbon, palladiumhydroxide-carbon, rhodium-carbon, platinum-carbon, Raney-nickel or thelike. The reducing agent is generally used in about 0.0001-100 mol,preferably about 0.01-10 mol, per 1 mol of compound (IIIb). Thisreaction is advantageously performed in a solvent inert to the reaction.Such solvent is not particularly limited as long as the reactionproceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides, aromatic organic bases and the like or a mixedsolvent thereof and the like are preferable.

(Step 3′)

Compound (Ia-I), which is the compound of the present invention, can beproduced by subjecting compound (IIIc) to a cyclization reaction. Thisreaction can be performed according to a manufacturing method known perse, for example, the method described in Australian Journal ofChemistry, vol. 4, page 775 (1982), Shinjikken Kagaku Koza (Courses inExperimental Chemistry), vols. 14 and 15 (The Chemical Society of Japaned.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMICPRESS, INC. (1989); Comprehensive Organic Transformations, VCHPublishers Inc. (1989) and the like, or a method analogous thereto. Forexample, a method using a carbonating agent can be mentioned. Examplesof the carbonating agent include 1,1′-carbonylbis(1H-imidazole),phosgene, triphosgene, diethyl carbonate, dimethyl carbonate,di-tert-butyl dicarbonate, bis(2,5-dioxopyrrolidin-1-yl)carbonate andthe like. The carbonating agent is generally used in about 0.2-5.0 mol,preferably about 0.5-2.0 mol, per 1 mol of compound (IIIc). In addition,a base can be used to promote the reaction. Examples of the base includeinorganic bases, organic bases, metal alkoxides, alkali metal hydrides,metal amides and the like. The base is used in about 1.0-20 mol,preferably about 1.0-5.0 mol, per 1 mol of compound (IIIc). Thisreaction is advantageously performed in a solvent inert to the reaction.Such solvent is not particularly limited as long as the reactionproceeds and, for example, solvents such as alcohols, ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides, aromatic organic bases, water and the like or amixed solvent thereof and the like are preferable. While the reactiontime varies depending on the reagent and solvent to be used, it isgenerally 10 min-72 hr, preferably 30 min-24 hr. The reactiontemperature is generally 0-200° C., preferably 0-100° C. In addition,microwave irradiation may be performed to promote the reaction.

(Step 8)

Compound (Ia-II), which is the compound of the present invention, can beproduced by reacting compound (Ia-I) with R^(d)—X⁴ in the presence of abase. The R^(d)—X⁴ is used in about 0.05-100 mol, preferably about0.1-10 mol, per 1 mol of compound (Ia-I). Examples of the base includeinorganic bases, basic salts, organic bases, metal amides and the like.The base is used in about 0.5-10.0 mol, preferably about 1.0-5.0 mol,per 1 mol of compound (Ia-I). To promote the reaction, for example,sodium iodide, potassium iodide and the like may be added. Such sodiumiodide, potassium iodide and the like are used in about 0.05-100 mol,preferably about 0.1-50 mol, per 1 mol of compound (Ia-I). This reactionis advantageously performed in a solvent inert to the reaction. Suchsolvent is not particularly limited as long as the reaction proceedsand, for example, solvents such as ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides and the like or a mixed solvent thereof and the like arepreferable. While the reaction time varies depending on the reagent andsolvent to be used, it is generally 10 min-100 hr, preferably 30 min-24hr. The reaction temperature is generally −20 to 250° C., preferably 0to 230° C. In addition, microwave irradiation may be performed topromote the reaction.

Compounds (IIIc), (IIa′), (IIIb) and (IIIc) may be commerciallyavailable products, or can be produced according to a method known perse or a method analogous thereto. In addition, R^(d)—X⁴ may be acommercially available product, or can also be produced by a knownsubstituent conversion reaction, condensation reaction, oxidationreaction, reduction reaction and the like, which may be used alone or ina combination of two or more thereof. These reactions may be performedaccording to, for example, the method described in Shinjikken KagakuKoza (Courses in Experimental Chemistry), vols. 14 and (The ChemicalSociety of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2ndedition, ACADEMIC PRESS, INC. (1989); Comprehensive OrganicTransformations, VCH Publishers Inc. (1989) and the like.

wherein X⁵ is a leaving group, and other symbols are as defined above.

Compound (Ia′), which is the compound of the present invention, can beproduced by subjecting compound (IVa) to the reaction step of Step 5′.

(Step 5′)

Compound (Ia′), which is the compound of the present invention, can beproduced by subjecting compound (IIf) and compound (IVa) to asubstitution reaction in the presence of a metal catalyst as necessary.Compound (IIf) is used in about 0.5-20 mol, preferably about 0.8-10 mol,per 1 mol of compound (IVa). As the metal catalyst, a metal complexhaving a variety of ligands is used and, for example, palladiumcompounds [e.g., palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,dichlorobis(triethylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II)acetate and 1,1′-bis(diphenylphosphino)ferrocene, complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(DavePhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(Xphos),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)(xantphos), ordicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane(SPhos), etc.],nickel compounds [e.g., tetrakis(triphenylphosphine)nickel (0),bis(triethylphosphine)nickel (II) chloride,bis(triphenylphosphine)nickel (II) chloride, etc.], rhodium compounds[e.g., tris(triphenylphosphine)rhodium (III) chloride, etc.], cobaltcompound, copper compounds [e.g., copper oxide, copper(I) iodide, coppersulfate, copper(II) chloride, etc.], platinum compound and the like canbe mentioned. Of these, a palladium compound and a copper compound arepreferable. The metal catalyst is used in about 0.0001-5 mol, preferablyabout 0.001-1 mol, per 1 mol of compound (IIf). This reaction ispreferably performed in the presence of a base. Examples of the baseinclude inorganic bases, organic bases, metal alkoxides, alkali metalhydrides, metal amides and the like. The base is used in about 1.0-20mol, preferably about 1.0-5.0 mol, per 1 mol of compound (IIf). Inaddition, when a metal catalyst unstable to oxygen is used in thisreaction, for example, the reaction is preferably performed in an inertgas stream such as argon gas, nitrogen gas and the like. This reactionis advantageously performed in a solvent inert to the reaction. Suchsolvent is not particularly limited as long as the reaction proceedsand, for example, solvents such as alcohols, ethers, aromatichydrocarbons, saturated hydrocarbons, amides, nitriles, sulfoxides,esters, water and the like or a mixed solvent thereof and the like arepreferable. While the reaction time varies depending on the reagent andsolvent to be used, it is generally 10 min-100 hr, preferably 30 min-50hr. The reaction temperature is −10 to 250° C., preferably 50 to 150° C.In addition, microwave irradiation may be performed to promote thereaction.

Compound (IIf) and compound (IVa) may be commercially availableproducts, or can also be produced according to the method described inShinjikken Kagaku Koza (Courses in Experimental Chemistry), vols. 14 and15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUPPREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., (1989); ComprehensiveOrganic Transformations, VCH Publishers Inc. (1989), Heterocycles, vol.4, page 799 (1985) and the like, or a method analogous thereto.

wherein W is an optionally substituted methylene group or a carbonylgroup, X⁶-X⁸ are each a leaving group, n is an integer of 1 to 5, andother symbols are as defined above. Examples of the substituent that the“methylene group” of the “optionally substituted methylene group” for Wmay have include 1 or 2 substituent selected from substituent group A.

Compound (Ia′-I) and compound (Ia′-II), which are the compounds of thepresent invention, can be produced by subjecting compound (Va) to aseries of reaction steps in Steps 6′, 9, 7′, 1″, 7″ and 3″, and Steps6′, 9, 7′, 1″, 7″, 3″ and 8′, respectively.

(Step 6′)

Compound (Vb) can be produced by subjecting compound (Va) and compound(Vh) to a substitution reaction. This reaction may be performedaccording to a method similar to that in (Step 6) above.

(Step 9)

Compound (Vd) can be produced by subjecting compound (Vb) and compound(Vc) to a substitution reaction. Compound (Vc) is used in about 0.5-10.0mol, preferably about 1.0-5.0 mol, per 1 mol of compound (Vb). Thisreaction can be performed in the presence of a base to promote thereaction. Examples of the base include inorganic bases, basic salts,organic bases, metal alkoxides, alkali metal hydrides, metal amides andthe like. The base is used in about 0.5-10.0 mol, preferably 0.8-5.0mol, per 1 mol of compound (Vb). In addition, to promote the reaction,for example, sodium iodide, potassium iodide and the like may be added.Such sodium iodide, potassium iodide and the like are used in about0.05-100 mol, preferably about 0.1-50 mol, per 1 mol of compound (Vc).This reaction is advantageously performed in a solvent inert to thereaction. Such solvent is not particularly limited as long as thereaction proceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides and the like or a mixed solvent thereof and thelike are preferable. While the reaction time varies depending on thereagent and solvent to be used, it is generally 10 min-100 hr,preferably 30 min-24 hr. The reaction temperature is generally −20 to250° C., preferably 0 to 230° C. In addition, microwave irradiation maybe performed to promote the reaction.

(Step 7′)

Compound (Ve) can be produced by subjecting compound (Vd) to a reductionreaction. This reaction may be performed according to a method similarto that in the above-mentioned (Step 7).

(Step 1″)

Compound (Vf) can be produced by reacting compound (Ve) with compound(IIa′). This reaction may be performed according to a method similar tothat in the above-mentioned (Step 1′).

(Step 7″)

Compound (Vg) can be produced by subjecting compound (Vf) to a reductionreaction. This reaction may be performed according to a method similarto that in the above-mentioned (Step 7).

(Step 3″)

Compound (Ia′-I), which is the compound of the present invention, can beproduced by subjecting compound (Vg) to a cyclization reaction. Thisreaction can be performed according to a manufacturing method known perse, for example, the method described in Bioorganic and MedicinalChemistry Letters, vol. 6, page 1702 (2009); Journal of MedicinalChemistry, vol. 13, page 3881 (2009); ORGANIC FUNCTIONAL GROUPPREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., (1989); ComprehensiveOrganic Transformations, VCH Publishers Inc. (1989) and the like, or amethod analogous thereto and, for example, a method using a carbonatingagent can be mentioned. Examples of the carbonating agent include1,1′-carbonylbis(1H-imidazole), phosgene, triphosgene, diethylcarbonate, dimethyl carbonate, di-tert-butyl dicarbonate and the like.The carbonating agent is generally used in about 0.2-5.0 mol, preferablyabout 0.5-2.0 mol, per 1 mol of compound (Vg). When an acidic substanceis released by the reaction, the reaction can be performed in thepresence of a deoxidizer to remove the substance from the reactionsystem. As such deoxidizer, inorganic bases, basic salts, organic bases,metal alkoxides, alkali metal hydrides, metal amides and the like areused. The deoxidizer is generally used in about 0.2-10 mol, preferablyabout 0.5-6.0 mol, per 1 mol of compound (Vg). This reaction isadvantageously performed in a solvent inert to the reaction. Suchsolvent is not particularly limited as long as the reaction proceedsand, for example, solvents such as ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides, aromatic organic bases and the like or a mixed solventthereof and the like are preferable. While the reaction time variesdepending on the reagent and solvent to be used, it is generally 10min-72 hr, preferably 30 min-24 hr. The reaction temperature isgenerally 0-200° C., preferably 0-100° C. In addition, microwaveirradiation may be performed to promote the reaction.

(Step 8′)

Compound (Ia′-II), which is the compound of the present invention, canbe produced by reacting compound (Ia′-I) with R^(d)—X⁸ in the presenceof a base. This reaction may be performed according to a method similarto that in the above-mentioned (Step 8).

Compounds (Va), (Vb), (Vc), (Vd), (Ve), (Vf) and (Vg) and R^(d)—X⁸ maybe commercially available products, or they can be produced according toa method known per se or a method analogous thereto. In addition,compound (Vc) can also be produced according to a known substituentconversion reaction, condensation reaction, oxidation reaction,reduction reaction and the like, which may be used alone or in acombination of two or more thereof. These reactions can also beperformed according to, for example, the method described in ShinjikkenKagaku Koza (Courses in Experimental Chemistry), vols. 14 and (TheChemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS,2nd edition, ACADEMIC PRESS, INC. (1989); Comprehensive OrganicTransformations, VCH Publishers Inc. (1989), Synthesis, vol. 7, page 577(1982), Journal of Organic Chemistry, vol. 1, page 284 (2007), RussianJournal of General Chemistry, vol. 9, page 1457 (2003) and the like.Compound (Vb) can also be produced according to the method described inTetrahedron Letters, vol. 22, page 3747 (2006) and the like, or a methodanalogous thereto.

wherein X⁹ is a leaving group, and other symbols are as defined above.

Compound (Ia′-III), which is the compound of the present invention, canbe produced by subjecting compound (IIh′) to a series of reaction stepsin Steps 10 and 11.

Compound (Ia′-III) can also be produced by subjecting compound (IIh′) toa series of reaction steps in Steps 10, 5″ and 11′.

(Step 10)

Compound (VIa) can be produced by reacting compound (IIh′) with atrifluoromethanesulfonylating agent. Examples of thetrifluoromethanesulfonylating agent includetrifluoromethanesulfonylchloride, trifluoromethanesulfonic anhydride,N-phenylbis(trifluoromethanesulfonimide),N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamideand the like. The trifluoromethanesulfonylating agent is generally usedin about 0.2-5.0 mol, preferably about 0.5-2.0 mol, per 1 mol ofcompound (IIh′). In addition, bases such as basic salts, organic basesand the like can be used to promote the reaction. The base is generallyused in about 0.2-20.0 mol, preferably about 0.5-10.0 mol, per 1 mol ofcompound (IIh′). This reaction is advantageously performed in a solventinert to the reaction. Such solvent is not particularly limited as longas the reaction proceeds and, for example, solvents such as ethers,aromatic hydrocarbons, saturated hydrocarbons, amides, halogenatedhydrocarbons, nitriles, sulfoxides, aromatic organic bases and the likeor a mixed solvent thereof and the like are preferable. While thereaction time varies depending on the reagent and solvent to be used, itis generally 10 min-72 hr, preferably 30 min-24 hr. The reactiontemperature is generally 0-100° C., preferably 0-70° C.

(Step 5″)

Compound (VIc) can be produced by condensing compound (VIa) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The condensation reaction isperformed by reacting compound (VIa) with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a metalcatalyst. The 4,4,5,5-tetramethyl-1,3,2-dioxaborolane is used in about0.1-10 mol, preferably about 0.8-2.0 mol, per 1 mol of compound (VIa).As the metal catalyst, palladium compound [e.g., palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,dichlorobis(triethylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II)acetate and 1,1′-bis(diphenylphosphino)ferrocene, complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(DavePhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(Xphos),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)(xantphos) ordicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane (SPhos) etc.] arepreferable. The metal catalyst is used in about 0.000001-5.0 mol,preferably about 0.0001-1.0 mol, per 1 mol of compound (VIa). Thisreaction is generally performed in the presence of a base. Examples ofthe base include inorganic bases, basic salts, organic bases, metalalkoxides, alkali metal hydrides, metal amides and the like. The base isused in about 1.0-20 mol, preferably about 1.0-5.0 mol, per 1 mol ofcompound (VIa). When a metal catalyst unstable to oxygen is used inthese reactions, the reaction is preferably performed, for example, inan inert gas stream such as argon gas, nitrogen gas and the like. Thisreaction is advantageously performed in a solvent inert to the reaction.Such solvent is not particularly limited as long as the reactionproceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, esters, water and the like or a mixed solvent thereof and thelike are preferable. While the reaction time varies depending on thereagent and solvent to be used, it is generally 1 min-200 hr, preferably5 min-100 hr. The reaction temperature is −10 to 250° C., preferably 0to 150° C. In addition, microwave irradiation may be performed topromote the reaction.

(Step 11)

Compound (Ia′-III), which is the compound of the present invention, canbe produced by condensing compound (VIa) and compound (VIb). Thecondensation reaction is performed by reacting compound (VIa) withcompound (VIb) in the presence of a metal catalyst. Compound (VIb) isused in about 0.1-10 mol, preferably about 0.8-2.0 mol, per 1 mol ofcompound (VIa). As the metal catalyst, palladium compound [e.g.,palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,dichlorobis(triethylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II)acetate and 1,1′-bis(diphenylphosphino)ferrocene, complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(DavePhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(Xphos),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)(xantphos) ordicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane(SPhos), etc.] ispreferable. The metal catalyst is used in about 0.000001-5.0 mol,preferably about 0.0001-1.0 mol, per 1 mol of compound (VIa). Thisreaction is generally performed in the presence of a base. Examples ofthe base include inorganic bases, basic salts and the like. The base isused in about 1.0-20 mol, preferably about 1.0-5.0 mol, per 1 mol ofcompound (VIa). When a metal catalyst unstable to oxygen is used inthese reactions, the reaction is preferably performed, for example, ininert gas stream such as argon gas, nitrogen gas and the like. Thisreaction is advantageously performed in a solvent inert to the reaction.Such solvent is not particularly limited as long as the reactionproceeds and, for example, solvents such as alcohols, ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, esters, water and the like or a mixed solvent thereof and thelike are preferable. While the reaction time varies depending on thereagent and solvent to be used, it is generally 1 min-200 hr, preferably5 min-100 hr. The reaction temperature is −10 to 250° C., preferably 0to 150° C. In addition, microwave irradiation may be performed topromote the reaction.

(Step 11′)

Compound which is the compound of the present invention, can be producedby reacting compound (VIc) with Ar—X⁹ in the presence of a base and ametal catalyst. This reaction may be performed according to a methodsimilar to that in the above-mentioned (Step 11).

Compounds (IIh′), (VIa), (VIb) and (VIc) and Ar—X⁹ may be commerciallyavailable products, or can also be produced according to a method knownper se or a method analogous thereto.

wherein X¹⁰ is a leaving group, and other symbols are as defined above.

Compound (Ib), which is the compound of the present invention, can beproduced by subjecting compound (VIIa) to the reaction step of Step 5′″.

(Step 5′″)

Compound (Ib), which is the compound of the present invention, can beproduced by reacting compound (VIIa) with compound (IIf) in the presenceof a base and a metal catalyst. This reaction may be performed accordingto a method similar to that in the above-mentioned (Step 5).

Compound (VIIa) and compound (IIf) may be commercially availableproducts, or can also be produced according to a method known per se ora method analogous thereto.

wherein X^(n) and X¹² are each a leaving group, and other symbols are asdefined above.

Compound (Ib-I), which is the compound of the present invention, can beproduced by subjecting compound (VIIIa) to the reaction steps in Steps4′, 8″, 2″ and 6′″.

(Step 4′)

Compound (VIIIb) can be produced by subjecting compound (VIIIa) andcompound (IIa″) to a condensation reaction, or to a coupling reaction inthe presence of a metal catalyst. This reaction can also be performedaccording to a manufacturing method known per se, the method describedin Synlett, vol. 13, page 2083 (2006) and the like, or a methodanalogous thereto. Compound (IIa″) is generally used in about 0.2-5.0mol, preferably about 0.5-2.0 mol, per 1 mol of compound (VIIIa). As themetal catalyst, a metal complex having a variety of ligands is used and,for example, palladium compounds [e.g., palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,dichlorobis(triethylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), complex of palladium(II)acetate and 1,1′-bis(diphenylphosphino)ferrocene, complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) anddichloromethane, complex of tris(dibenzylideneacetone)dipalladium(0) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(DavePhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(Xphos),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)(Xantphos) ordicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane(SPhos), etc.],nickel compounds [e.g., tetrakis(triphenylphosphine)nickel (0),bis(triethylphosphine)nickel (II) chloride,bis(triphenylphosphine)nickel (II) chloride, etc.], copper compounds[e.g., copper oxide, copper(I) iodide, copper sulfate, copper(II)chloride, etc.] and the like can be mentioned. The metal catalyst isused in about 0.0001-5 mol, preferably about 0.001-1 mol, per 1 mol ofcompound (IIf). This reaction is preferably performed in the presence ofa base. Examples of the base include inorganic bases, organic bases,metal alkoxides, alkali metal hydrides, metal amides and the like. Thisreaction is advantageously performed in a solvent inert to the reaction.Such solvent is not particularly limited as long as the reactionproceeds and, for example, solvents such as alcohols, ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides, aromatic organic bases and the like or a mixedsolvent thereof and the like are preferable. In addition, when an acidicsubstance is released by the reaction, the reaction can be performed inthe presence of a deoxidizer to remove the substance from the reactionsystem. As such deoxidizer, for example, inorganic bases, basic salts,organic bases, metal alkoxides, alkali metal hydrides, metal amides andthe like are used. The deoxidizer is generally used in about 0.05-20mol, preferably about 1-10 mol, per 1 mol of compound (VIIIa). Inaddition, for example, basic salts, organic bases and the like can beused to promote the reaction. Such basic salts, organic bases and thelike are generally used in about 0.05-20 mol, preferably about 1-10 mol,per 1 mol of compound (VIIIa). While the reaction time varies dependingon the reagent and solvent to be used, it is generally 10 min-200 hr,preferably 30 min-48 hr. The reaction temperature is generally 0-200°C., preferably 50-150° C. In addition, microwave irradiation may beperformed to promote the reaction.

(Step 8″)

Compound (VIIIc) can be produced by reacting compound (VIIIb) withR^(d)—X¹¹ in the presence of a base. This reaction can be performedaccording to a method similar to that in the above-mentioned (Step 8).

(Step 2″)

Compound (VIIId) can be produced by removing the protective group (P³)of compound (VIIIc). When P³ is a hydrogen atom, this step can beomitted. This reaction can be performed according to a method similar tothat in the above-mentioned (Step 2).

(Step 6″)

Compound (Ib-I), which is the compound of the present invention, can beproduced by reacting compound (VIIId) with R²—X¹² in the presence of abase. This reaction may be performed according to a method similar tothat in the above-mentioned (Step 6).

Compounds (VIIIa), (IIa″), (VIIIb), (VIIIc) and (VIIId), and R^(d)—X¹¹and R²—X¹² may be commercially available products, or can also beproduced according to a method known per se or a method analogousthereto.

wherein X¹³ and X¹⁴ are each a leaving group, and the other symbols areas defined above.

Compound (Ia-III), which is the compounds of the present invention, canbe produced by subjecting compound (IIIa′) to a series of reaction stepsin Steps 1′″, 7′″, 3′″, 8′″, 2′″, and 6′″.

(Step 1′″)

Compound (IIIb′) can be produced by reacting compound (IIIa′) withcompound (IIa′). Compound (IIIa′) is generally used in about 0.2-5.0mol, preferably about 0.5-2.0 mol, per 1 mol of compound (IIa′). Thisreaction is advantageously performed in a solvent inert to the reaction.The solvent is not particularly limited as long as the reaction proceedsand, for example, solvents such as ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides, aromatic organic bases and the like or a mixed solventthereof and the like are preferable. In addition, when an acidicsubstance is released by the reaction, the reaction can be performed inthe presence of a deoxidizer to remove the substance from the reactionsystem. As the deoxidizer, for example, inorganic bases, basic salts,organic bases, metal alkoxides, alkali metal hydrides, metal amides andthe like are used. The deoxidizer is generally used in about 0.05-20mol, preferably about 0.1-10 mol, per 1 mol of compound (IIa′). Inaddition, for example, basic salts, organic bases and the like can alsobe used to promote the reaction. Such basic salts, organic bases and thelike are generally used in about 0.05-20 mol, preferably about 0.1-10mol, per 1 mol of compound (IIa′). While the reaction time variesdepending on the reagent and solvent to be used, it is generally 10min-72 hr, preferably 30 min-24 hr. The reaction temperature isgenerally 0-200° C., preferably 50-150° C. In addition, microwaveirradiation may be performed to promote the reaction.

(Step 7′″)

Compound (IIIc′) can be produced by subjecting compound (IIIb′) to areduction reaction. This reaction can be performed according to a methodknown per se such as the method described in Shinjikken Kagaku Koza(Courses in Experimental Chemistry), vols. 14 and 15 (The ChemicalSociety of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2ndedition, ACADEMIC PRESS, INC. (1989); Comprehensive OrganicTransformations, VCH Publishers Inc. (1989) and the like, or a methodanalogous thereto. For example, a method using a reducing agent can bementioned. Examples of the reducing agent include zinc, tin chloride,and complexes of hydrogen and, for example, palladium-carbon, palladiumhydroxide-carbon, rhodium-carbon, platinum-carbon, Raney-nickel or thelike. The reducing agent is generally used in about 0.0001-100 mol,preferably about 0.01-10 mol, per 1 mol of compound (IIIb′). Thisreaction is advantageously performed in a solvent inert to the reaction.Such solvent is not particularly limited as long as the reactionproceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides, aromatic organic bases and the like or a mixedsolvent thereof and the like are preferable.

(Step 3′″)

Compound (IIIe) can be produced by subjecting compound (IIIc′) to acyclization reaction. This reaction can be produced according to amanufacturing method known per se, for example, the method described inAustralian Journal of Chemistry, vol. 4, page 775 (1982), ShinjikkenKagaku Koza (Courses in Experimental Chemistry), vols. 14 and 15 (TheChemical Society of Japan ed.), ORGANIC FUNCTIONAL GROUP PREPARATIONS,2nd edition, ACADEMIC PRESS, INC. (1989); Comprehensive OrganicTransformations, VCH Publishers Inc. (1989) and the like, or a methodanalogous thereto. For example, a method using a carbonating agent canbe mentioned. Examples of the carbonating agent include1,1′-carbonylbis(1H-imidazole), phosgene, triphosgene, diethylcarbonate, dimethyl carbonate, di-tert-butyl dicarbonate,bis(2,5-dioxopyrrolidin-1-yl)carbonate and the like. The carbonatingagent is generally used in about 0.2-5.0 mol, preferably about 0.5-2.0mol, per 1 mol of compound (IIIc′). In addition, a base can be used topromote the reaction. Examples of the base include inorganic bases,organic bases, metal alkoxides, alkali metal hydrides, metal amides andthe like. The base is used in about 1.0-20 mol, preferably about 1.0-5.0mol, per 1 mol of compound (IIIc′). This reaction is advantageouslyperformed in a solvent inert to the reaction. Such solvent is notparticularly limited as long as the reaction proceeds and, for example,solvents such as alcohols, ethers, aromatic hydrocarbons, saturatedhydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides,aromatic organic bases, water and the like or a mixed solvent thereofand the like are preferable. While the reaction time varies depending onthe reagent and solvent to be used, it is generally 10 min-72 hr,preferably 30 min-24 hr. The reaction temperature is generally 0-200°C., preferably 0-100° C. In addition, microwave irradiation may beperformed to promote the reaction.

(Step 8′″)

Compound (IIIf) can be produced by reacting compound (IIIe) withR^(d)—X¹³ in the presence of a base. R^(d)—X¹³ is used in about 0.05-100mol, preferably about 0.1-10 mol, per 1 mol of compound (IIIe). Examplesof the base include inorganic bases, basic salts, organic bases, metalamides and the like. The base is used in about 0.5-10.0 mol, preferablyabout 1.0-5.0 mol, per 1 mol of compound (IIIe). To promote thereaction, for example, sodium iodide, potassium iodide and the like maybe added. Such sodium iodide, potassium iodide and the like are used inabout 0.05-100 mol, preferably about 0.1-50 mol, per 1 mol of compound(IIIe). This reaction is advantageously performed in a solvent inert tothe reaction. Such solvent is not particularly limited as long as thereaction proceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides and the like or a mixed solvent thereof and thelike are preferable. While the reaction time varies depending on thereagent and solvent to be used, it is generally 10 min-100 hr,preferably 30 min-24 hr. The reaction temperature is generally −20 to250° C., preferably 0 to 230° C. In addition, microwave irradiation maybe performed to promote the reaction.

(Step 2′″)

Compound (IIIg) can be produced by removing the protective group (P¹) ofcompound (IIIf). When P¹ is a hydrogen atom, this step can be omitted.This reaction may be performed according to a method similar to that ofthe above-mentioned (Step 2).

(Step 6′″)

Compound (Ia-III), which is the compound of the present invention, canbe produced by subjecting compound (IIIg) and R¹—X¹⁴ to a substitutionreaction in the presence of a base. R¹-R¹⁴ is used in about 0.05-100mol, preferably about 0.1-10 mol, per 1 mol of compound (IIIg). Examplesof the base include inorganic bases, basic salts, organic bases, metalamides, alkali metal hydrides and the like. The base is used in about0.5-10.0 mol, preferably about 1.0-5.0 mol, per 1 mol of compound(IIIg). This reaction is advantageously performed in a solvent inert tothe reaction. The solvent is not particularly limited as long as thereaction proceeds and, for example, solvents such as ethers, aromatichydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons,nitriles, sulfoxides and the like or a mixed solvent thereof and thelike are preferable. While the reaction time varies depending on thereagent and solvent to be used, it is generally 10 min-100 hr,preferably 30 min-24 hr. The reaction temperature is generally-20-250°C., preferably 0-230° C. In addition, microwave irradiation may beperformed to promote the reaction.

Compounds (IIIa′), (IIa′), (IIIb′), (IIIc′), (IIIe), (IIIf) and (IIIg)may be commercially available products, or can be produced according toa method known per se or a method analogous thereto. In addition,R^(d)—X¹³ and R¹-X¹⁴ may be commercially available products, or can alsobe produced by a known substituent conversion reaction, condensationreaction, oxidation reaction, reduction reaction and the like, which maybe used alone or in a combination of two or more thereof. Thesereactions may be performed according to, for example, the methoddescribed in Shinjikken Kagaku Koza (Courses in Experimental Chemistry),vols. 14 and 15 (The Chemical Society of Japan ed.), ORGANIC FUNCTIONALGROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (1989);Comprehensive Organic Transformations, VCH Publishers Inc. (1989) andthe like.

Compound (I) obtained by the above-mentioned methods can be isolated andpurified by, for example, general separation means such asrecrystallization, distillation, chromatography and the like. When thethus-obtained compound (I) of the present invention is in a free form,it can be converted to a salt thereof by a known method or a comparablemethod (e.g., neutralization etc.). Alternatively, when it is obtainedas a salt, it can be converted to a free form or other salt by a knownmethod or a comparable method.

In any of the above-mentioned manufacturing methods and steps, compound(I) can be synthesized by known protection and deprotection reactions,acylation reaction, alkylation reaction, hydrogenation reaction,oxidation reaction, reduction reaction, carbon chain extension reaction,substituent exchanging reactions and the like, which may be used aloneor in a combination of two or more thereof.

Compound (I) may be used as a prodrug. A prodrug of compound (I) means acompound converted to compound (I) by a reaction due to an enzyme, agastric acid, etc. under the physiological condition in the living body,that is, a compound converted to compound (I) by oxidation, reduction,hydrolysis, etc. due to an enzyme, a compound converted to compound (I)by hydrolysis etc. due to gastric acid, and the like.

A prodrug of compound (I) may be a compound obtained by subjecting anamino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy group in thecompound (I) to acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation ordimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxy group in compound (I) to esterification oramidation (e.g., a compound obtained by subjecting a carboxy group incompound (I) to ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification ormethylamidation, etc.) and the like. Any one of these compounds can beproduced from compound (I) by a method known per se. In addition, aprodrug of compound (I) may also be a compound converted into compound(I) under physiological conditions, such as those described in IYAKUHINno KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design ofMolecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

The compound of the present invention has an excellent PDE10A inhibitoryactivity and is useful for the following diseases and symptoms inmammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, rats,etc. particularly in humans):

psychotic disorder (e.g., brief psychotic disorder, shared psychoticdisorder);

psychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, obesity, inhalants, opioids, or phencyclidine;

delusional disorder;

anxiety disorder;

movement disorder;

mood disorder;

major depressive disorder;

a major depressive disorder superimposed on a psychotic disordercomprising a delusional disorder or schizophrenia;

major depressive episode of the mild, moderate or severe type;

manic or mixed mood episode;

hypomanic mood episode;

depressive episode with atypical features;

depressive episode with melancholic features;

depressive episode with catatonic features;

mood episode with postpartum onset;

post-stroke depression;

dysthymic disorder;

minor depressive disorder;

autism;

drug addiction;

neurodegenerative disorder;

neurodegeneration associated with cerebral trauma;

neurodegeneration associated with stroke;

neurodegeneration associated with cerebral infarct;

hypoglycemia-induced neurodegeneration;

neurodegeneration associated with epileptic seizure;

neurodegeneration associated with neurotoxin poisoning;

multi-system atrophy;

Alzheimer's disease;

dementia;

multi-infarct dementia;

alcoholic dementia or other drug-related dementia;

dementia associated with intracranial tumors or cerebral trauma;

dementia associated with Huntington's disease or Parkinson's disease;

AIDS-related dementia;

frontotemporal dementia;

delirium;

amnestic disorder;

post-traumatic stress disorder;

mental retardation;

learning disorder (e.g., reading disorder, mathematics disorder, or adisorder of written expression);

attention-deficit/hyperactivity disorder;

age-related cognitive decline;

premenstrual dysphoric disorder;

post-psychotic depressive disorder of schizophrenia;

bipolar disorders comprising bipolar I disorder, and bipolar IIdisorder;

cyclothymic disorder;

Parkinson's disease;

Huntington's disease;

paranoid;

schizophrenia (e.g., paranoid schizophrenia, disorganized schizophrenia,catatonic schizophrenia, undifferentiated schizophrenia, residualschizophrenia);

schizophreniform disorder;

schizoaffective disorder of the delusional type or the depressive type;

personality disorder of the paranoid type;

personality disorder of the schizoid type;

obesity;

metabolic syndrome;

non-insulin dependent diabetes mellitus (NIDDM);

glucose intolerance;

In particular, the compound of the present invention is useful forpreventing or treating schizophrenia.

Since the compound of the present invention demonstrates excellentmetabolic stability, superior therapeutic effects on the aforementioneddiseases are expected even at a low dosage.

The compound of the present invention shows low toxicity and can beadministered safely, as it is, or in a dosage form which is manufacturedaccording to a per se known method for manufacturing pharmaceuticalformulations (e.g., methods described in Japanese Pharmacopoeia) such astablets (inclusive of sugar coated tablet, film coated tablet,sublingual tablet, orally disintegrable tablet, and buccal), pills,powders, granules, capsules (inclusive of soft capsule, andmicrocapsule), troches, syrups, liquid dosage forms, emulsions,controlled-release preparations (e.g., quick-release preparation,sustained-release preparation, sustained-release microcapsule),aerosols, films (e.g., orally disintegrable film, adhesive film forapplication to oral-cavity mucosa), injections (e.g., subcutaneousinjection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, percutaneous absorbent,ointment, lotion, patch, suppositories (e.g., rectal suppository,vaginal suppository), pellets, transnasal preparations, pulmonarypreparations (inhalant), eye drops and the like, in an oral orparenteral route (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, ophthalmic instillation,intracerebral, intrarectal, intravaginal, intraperitoneal, directly tolesion).

The compound of the present invention can be administered orally ornon-orally (e.g., including local, rectal and venous routes).

Here, as a pharmaceutical acceptable carrier, common organic orinorganic carrier substances are used as formulation raw materials.Carriers are added as vehicles, lubricants, binders and disintegrants inthe solid formulations; and as solvents, solubilizing agents, suspendingagents, isotonization agents, buffers and soothing agents in the liquidformulations. If desired, formulation additives such as antiseptics,antioxidants, colorants, sweeteners, etc. can be used.

Favorable examples of the vehicles are as follows: lactose, sucrose,D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystallinecellulose, low-substituted hydroxypropyl cellulose, sodiumcarboxymethylcellulose, gum Arabic, pullulan, light silicic anhydride,synthetic aluminum silicate and magnesium metasilicic aluminate.

Favorable examples of the lubricants include magnesium stearate, calciumstearate, talc and colloidal silica.

Favorable examples of the binders are as follows: α-starch, sucrose,gelatin, gum Arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose,dextrin, pullulan, hydroxypropylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

Favorable examples of the disintegrants are as follows: lactose,sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light silicicanhydride and low-substituted hydroxypropylcellulose.

Favorable examples of the solvents are as follows: water for injection,physiological saline, Linger solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Favorable examples of the solubilizing agents are as follows:polyethylene glycol, propylene glycol, D-mannitol, trehalose,benzylbenzoate, ethanol, tris-aminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate, sodium salicylate andsodium acetate.

Favorable examples of the suspending agents are as follows: surfactantssuch as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,and glycerin monostearate; hydrophilic polymers such as polyvinylalcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose,methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose andhydroxypropyl cellulose; polysorbates, and polyoxyethylene-hardenedcastor oil.

Favorable examples of the isotonization agents include sodium chloride,glycerin, D-mannitol, D-sorbitol and glucose.

Favorable examples of the buffers include buffer solutions ofphosphates, acetates, carbonates and citrates.

Favorable examples of the soothing agents include benzyl alcohol.

Favorable examples of the antiseptics include para-oxybenzoic acidesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid and sorbic acid.

Favorable examples of the antioxidants include sulfites and ascorbates.

Favorable examples of the colorants include water soluble edible tardyes (e.g., edible dyes such as Food Red No. 2 and No. 3, Food YellowNo. 4 and No. 5, Food Blue No. 1 and 2); water insoluble lake dyes(e.g., aluminum salts of the aforementioned water soluble edible tardyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide).

Favorable examples of the sweeteners include sodium saccharin,dipotassium glycyrrhizate, aspartame and stevia.

The medical compositions of the present invention can be manufactured bythe common methods in the field of formulation technology, for example,methods listed in the Japanese pharmacopoeia. Specific manufacturingmethods for formulations are described in detail below.

The content of the compound of the present invention in the medicalcompositions of the present invention varies based on the dosage forms,dosages of the compound of the present invention, etc. For example, thecontent approximately ranges from 0.01 to 100 wt % and preferably from0.1 to 95 wt % relative to the entire amount of the composition.

The dosage of the compound of the present invention depends uponinjection targets, administration routes, target diseases, symptoms,etc. For example, in the case of oral administration in patients withschizophrenia (adults, bodyweight of approximately 60 kg), generally asingle dose ranges from approximately 0.1 to 20 mg/kg bodyweight,preferably from approximately 0.2 to 10 mg/kg bodyweight, furtherpreferably from approximately 0.5 to 10 mg/kg bodyweight, and thisdosage is preferably administered once daily or several times daily(e.g., 3 times).

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of psychosis, especially schizophrenia and bipolardisorder, obsessive-compulsive disorder, major depression, Parkinson'sdisease, Alzheimer's disease, cognitive impairment and/or memory loss,e.g., nicotinic α7 agonists, nicotinic α7 partial agonists, nicotinic α7positive allosteric modulators, PDE2 inhibitors, PDE4 inhibitors, PDE5inhibitors, other PDE inhibitors, calcium channel blockers, muscarinicm1 and m2 modulators, adenosine receptor modulators, ampakines, Glycinetransporter 1 inhibitors, NMDA-R modulators, mGluR modulators, dopaminemodulators, serotonin modulators, selective serotonin reuptakeinhibitors, serotonin and norepinephrine reuptake inhibitors,norepinephrine and dopamine reuptake inhibitors, triple reuptakeinhibitors, cannabinoid modulators, and cholinesterase inhibitors (e.g.,donepezil, rivastigimine, and galantamine). In such combinations, eachactive ingredient can be administered either in accordance with theirusual dosage range or a dose below their usual dosage range, and can beadministered either simultaneously or sequentially.

Drugs suitable in combination with the compounds of the presentinvention include, but are not limited to, other suitable schizophreniadrugs such as Haloperidol, Clozapine, Olanzapine, Risperidone,Aripiprazole, Ziprasidone, Paliperidone, and Quetiapine fumarate;bipolar disorder drugs, including, but not limited to, Lithium,Olanzapine, Aripiprazole, and Valproic acid; Parkinson's disease drugs,including, but not limited to, Levodopa, Bromocriptine, Pergolide,Pramipexole, Tolcapone, Procyclidine, Trihexyphenidyl, and Benztropine;agents used in the treatment of major depression, including, but notlimited to, Amitriptyline, Protriptyline, Desipramine, Nortriptyline,Paroxetine, Fluoxetine, Sertraline, Bupropion, Escitalopram,Mirtazapine, Venlafaxine, Duloxetine; agents used in the treatment ofAlzheimer's disease, including, but not limited to, Galantamine,Tacrine, Donepezil, Rivastigmine, Memantine, Neotropin, Selegiline,Estrogen and Iodoquinol; agents used in the treatment of dementia,including, but not limited to, Thioridazine, Haloperidol, Risperidone,Tacrine, Donepezil, and Rivastigmine; agents used in the treatment ofepilepsy, including, but not limited to, Phenyloin, Phenobarbital,Carbamazepine, Valproic acid, Ethosuximide, Gabapentin, Phenobarbital,Solfeton and Felbatol; agents used in the treatment of multiplesclerosis, including, but not limited to, Tolterodine, Oxybutynin,Oxycodone, Interferon beta-1b, Interferon beta-1a, Azathioprine,Methotrexate and Glatiramer; agents used in the treatment ofHuntington's disease, including, but not limited to, Amitriptyline,Protripthline, Desipramine, Nortriptyline, Paroxetine, Fluoxetine,Setraline, Tetrabenazine, Haloperidol, Chlorpromazine, Thioridazine,Sulpiride, Quetiapine, Clozapine, and Risperidone; agents useful in thetreatment of diabetes, including, but not limited to, PPAR ligands (e.g.agonists, antagonists, such as Rosiglitazone, Troglitazone andPioglitazone), insulin secretagogues (e.g., sulfonylurea drugs, such asGlyburide, Glimepiride, Chlopropamide, Tolbutamide, and Glipizide, andnon-sulfonyl secretagogues), α-glucosidase inhibitors (such as Acarbose,Miglitol, and Voglibose), insulin sensitizers (such as the PPAR-γagonists, e.g., the glitazones; biguanides, PTP-1B inhibitors, DPP-IVinhibitors, and llbeta-HSD inhibitors), hepatic glucose output loweringcompounds (such as glucagon antagonists and metformin, e.g., Glucophageand Glucophage XR), insulin and insulin derivatives (both long and shortacting forms and formulations of insulin); and antiobesity drugs,including, but not limited to, β-3 agonists, CB-1 agonists, neuropeptideY5 inhibitors, Ciliary Neurotrophic Factor and derivatives (e.g.,Axokine), appetite suppressants (e.g., Sibutramine), and lipaseinhibitors (e.g., Orlistat).

The form of administration of concomitant drugs with the compound of thepresent invention is not particularly limited and is acceptable as longas the compound of the present invention is combined with concomitantdrugs at the time of administration. Examples of such forms ofadministration are as follows:

(1) administration of a single formula obtained by simultaneousformulation of the compound of the present invention with a concomitantdrug,

(2) simultaneous administration via the same administration route fortwo kinds of formulas obtained by independent formulations of thecompound of the present invention and a concomitant drug,

(3) administrations at different times via the same administration routefor two kings of formulas obtained by independent formulations of thecompound of the present invention and a concomitant drug,

(4) simultaneous administration via different administration routes fortwo kinds of formulas obtained by independent formulations of thecompound of the present invention and a concomitant drug,

(5) administrations at different times via different administrationroutes for two kinds of formulas obtained by independent formulations ofthe compound of the present invention and a concomitant drug (Forexample, administration in the order of the composition of the presentinvention and then a concomitant drug, or administration in the reversedorder). These forms of administration are summarized below andabbreviated as a concomitant agent of the present invention.

When administering the concomitant agent of the present invention, aconcomitant drug and the compound of the present invention can beadministered at the same time, but the compound of the present inventioncan be administered after a concomitant drug is administered or afterthe compound of the present invention is administered, a concomitantdrug can be administered. When administering at different times, thetime difference depends upon the active ingredients to be administered,drug forms and methods of administration. For example, when aconcomitant drug is administered first, the compound of the presentinvention can be administered within 1 min to 3 days, preferably within10 min to 1 day and more preferably within 15 min to 1 hour after theconcomitant drug is administered. However, if the compound of thepresent invention is administered first, a concomitant drug can beadministered within 1 min to 1 day, preferably within 10 min. to 6 hoursand more preferably within 15 min to 1 hour after the compound of thepresent invention is administered.

If there are no problems with side effects of the concomitant drugs, anydosages can be set. A daily dosage as a concomitant drug depends upondosages, administration subjects, administration routes, targetdiseases, symptoms, etc. For example, in the case of oral administrationin patients with schizophrenia (adults, bodyweight of approximately 60kg), a normal daily dosage ranges from about 0.1 to 20 mg/kg bodyweight,preferably from about 0.2 to 10 mg/kg bodyweight and more preferablyfrom about 0.5 to 10 mg/kg bodyweight. It is preferable that this dosageis administered once daily to several times daily (e.g., 3 times).

If the compound of the present invention is used in combination with aconcomitant drug, the respective dosages can be reduced within a saferange with consideration of the opposite effects of the respectivedrugs.

The concomitant agent of the present invention exhibits low toxicity.For example, the compound of the present invention or(and) theaforementioned concomitant drug can be combined with a pharmaceuticallyacceptable carrier according to the known method to prepare a medicalcomposition such as tablets (including sugar-coated tablets andfilm-coated tablets), powder agents, granular agents, capsules(including soft capsules), liquids, injection solutions, suppositories,sustained-release agents, etc. These compositions can be administeredsafely orally or non-orally (e.g., including local, rectal and venousroutes).

The pharmaceutically acceptable carriers that can be used formanufacturing the concomitant agent of the present invention can be thesame as those used in the medical composition of the present inventionas mentioned above.

A mixing ratio between the compound of the present invention and aconcomitant drug in the concomitant agent of the present invention canbe selected appropriately based on the administration subjects,administration routes and diseases.

The aforementioned concomitant drugs can be combined at an appropriateproportion if two or more drugs are combined.

A dosage of the concomitant drug can be selected appropriately based onthe dosages used clinically. In addition, a mixing ratio between thecompound of the present invention and a concomitant drug can be selectedappropriately based on the administration subjects, administrationroutes, target diseases, symptoms, combinations, etc. For example, ifthe administration subject is humans, a concomitant drug can be used inan amount ranging from 0.01 to 100 parts by weight relative to 1 part byweight of the compound of the present invention.

For example, the content of the compound of the present invention in theconcomitant agent of the present invention varies with the drug form offormulations. Generally, it is present in a range from about 0.01 to99.9 wt %, preferably from about 0.1 to 50 wt % and more preferably fromabout 0.5 to wt % relative to the entire formula.

The content of a concomitant drug in the concomitant agent of thepresent invention varies with the drug form of formulations. Generallyit is present in a range from about 0.01 to 99.9 wt %, preferably fromabout 0.1 to 50 wt % and more preferably from about 0.5 to 20 wt %relative to the entire formula.

The content of an additive such as carriers in the concomitant agent ofthe present invention varies with the drug form of formulations.Generally it is present in a range from about 1 to 99.99 wt % andpreferably from about 10 to 90 wt % relative to the entire formula.

When the compound of the present invention and a concomitant drug areformulated independently, the same contents can be applied.

Since the dosages may fluctuate under various conditions as mentionedabove, a dosage less than the aforementioned dosages may be sufficientor it may be necessary to administer at a dosage exceeding the range.

EXAMPLES

The present invention is explained in detail by referring m to thefollowing Reference Examples, Examples, Formulation Examples, andExperimental Examples. These examples are mere embodiments, which do notlimit the present invention, and can be modified within the range notdeviating from the scope of the present invention.

The “room temperature” in the following Reference Examples and Examplesis generally about 10° C. to about 35° C. in the yield means mol/mol %,% of solvent used for chromatography means % by volume, and % used forothers means wt %. In proton NMR spectrum, OH and NH protons and thelike that cannot be identified since they are broad bands are notrecorded in the data. In silica gel chromatography, Kiesselgel 60manufactured by Merck & Co., Inc. was used, and Chromatorex NHmanufactured by Fuji Silysia Chemical Ltd. was used in basic silica gelchromatography.

Other abbreviations used in the text mean the following.

-   -   s: singlet    -   d: doublet    -   dd: doublet of doublets    -   dt: doublet of triplets    -   t: triplet    -   tt: triplet of triplets    -   td: triplet of doublets    -   q: quartet    -   septet: septet    -   m: multiplet    -   br: broad    -   J: coupling constant    -   Hz: Hertz    -   CDCl₃: deuterated chloroform    -   DMSO-d₆: deuterated dimethyl sulfoxide    -   ¹H NMR: proton nuclear magnetic resonance    -   HPLC: high performance liquid chromatography    -   THF: tetrahydrofuran    -   DMF: N,N-dimethylformamide    -   DMSO: dimethyl sulfoxide    -   DMA: N,N-dimethylacetamide    -   DIEA: diisopropylethylamine    -   NMP: N-methylpyrrolidone    -   Boc₂O: di-tert-butyl dicarbonate    -   DMAP: 4-dimethylaminopyridine    -   TEA: triethylamine    -   NaHMDS: sodiumbis(trimethylsilyl)amide    -   mCPBA: meta-chloroperbenzoic acid    -   DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium        chloride n-hydrate    -   CDI: 1,1′-carbonylbis(1H-imidazole)    -   DBU: 1,8-diazabicyclo[5.4.0]-7-undecene    -   Pd(Ph₃P)₄: tetrakis(triphenylphosphine)palladium(0)    -   Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)    -   TBAF: tetra-n-butylammonium fluoride    -   TMEDA: tetramethylethylenediamine    -   IPE: diisopropyl ether    -   DME: 1,2-dimethoxyethane    -   DIPEA: N,N-diisopropylethylamine    -   LC-MS: liquid chromatography-mass spectrometry spectrum    -   ESI: electrospray-ionization method    -   aq.: aqueous solution    -   sat.: saturated    -   rt: room temperature

All reagents and solvents were of commercial quality and used withoutfurther purification. Column chromatography was performed using Mercksilica gel 60 (230-400 mesh). The compounds and/or intermediates werepurified by preparative high performance liquid chromatography (prep.HPLC) using a Gilson High through Put purification system.

The columns were reversed phase YMC CombiPrep Pro C18, S-5 μm, 19×50 mm.A gradient elution was used (flow rate 20 mL/min), typically startingwith 5% acetonitrile/95% water and progressing to 100% acetonitrile overa Period of 7 minutes. All solvents contained 0.1% trifluoroacetic acid(TFA).

Mass spectrometric analysis was performed according to liquidchromatography/mass spectroscopy (LCMS) methods. The method employed aWaters LC-MS System (Agilent HP1100 HPLC and a Micromass ZMD massspectrometer for the LCMS instrument, a CAPCELL PAK C18, UG120, S-3 μm,1.5×35 mm for the chromatography column), and a solvent system that wasa 5-95% gradient of acetonitrile in water with 0.04% TFA over a 3.60 minperiod (flow rate 0.5 mL/min molecular weight range 200-800; coneVoltage 20 V; column temperature 40° C.). All masses were reported asthose of the protonated parent ions.

Example Example 13-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

1a) N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine

To a solution of benzene-1,4-diamine (5.0 g) in NMP (30 ml) was addeddropwise, over 0.5 h, a solution of 2-chlorobenzo[d]oxazole (6.03 g) inNMP (50 ml). After the addition was complete, the mixture was stirred atambient temperature for 1 h. After this time, the reaction mixture wasdiluted with water (200 mL) and extracted with ethyl acetate (3×200 mL).The combined organic extracts were washed with brine (150 ml), dried(Na₂SO₄) and filtered. The filtrate was concentrated under reducedpressure. The residue obtained was purified by chromatography (silica,methylene chloride to 1:19 methanol/methylene chloride) to affordN-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (9.20 g) as an off-whitesolid.

MS (ESI+): [M+H]⁺ 226.

1b) N-(1,3-benzoxazol-2-yl)-N′-(3-nitropyridin-2-yl)benzene-1,4-diamine

A mixture of N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (0.50 g) and2-chloro-3-nitropyridine (0.352 g) in NMP (3.0 ml) was stirred at 140°C. for 1.5 h. After this time, the reaction mixture was cooled toambient temperature, diluted with water (50 ml), and extracted withethyl acetate (3×100 ml). The combined organic extracts were washed withbrine (100 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue obtained was purified by chromatography (silica,methylene chloride to 1:9 ethyl acetate/methylene chloride) to affordN-(1,3-benzoxazol-2-yl)-N′-(3-nitropyridin-2-yl)benzene-1,4-diamine(0.335 g) as a red solid.

MS (ESI+): [M+H]⁺ 348.

1c) N²-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine

A solution ofN-(1,3-benzoxazol-2-yl)-N′-(3-nitropyridin-2-yl)benzene-1,4-diamine(0.330 g) in methanol (20 mL) was treated with palladium on carbon(0.060 g, 10% wt on activated carbon) and the mixture was hydrogenated(1 atm H₂) for 1 h. After this time, the reaction mixture was filteredthrough diatomaceous earth. The filtrate was concentrated under reducedpressure to affordN²-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.294 g) asa yellow solid.

MS (ESI+): [M+H]⁺ 318.

1d)3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture ofN²-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.080 g)and triethylamine (0.0638 g) in THF (1.5 mL) at 0° C., was addeddropwise a solution of triphosgene (0.030 g) in THF (0.6 mL). Thereaction mixture was stirred at 0° C. for 0.5 h. The cold bath wasremoved and the stirring continued at ambient temperature for another0.5 h. After this time, a saturated aqueous solution of sodiumbicarbonate was added. The organic layer was extracted with ethylacetate (3×100 ml). The combined organic extracts were washed with brine(50 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue obtained was purified by chromatography (silica,methylene chloride to 0.3:5:95 ammonium hydroxide/methanol/methylenechloride) to afford3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.038 g) as a white solid.

MS (ESI+): [M+H]⁺ 344.

¹H NMR (500 MHz, DMSO-d₆) δ 7.08 (1H, dd, J=8.0, 5.5 Hz), 7.15 (1H, dt,J=7.5, 1.0 Hz), 7.24 (1H, dt, J=7.5, 1.0 Hz), 7.39 (1H, dd, J=7.5, 1.5Hz), 7.48 (1H, d, J=7.5 Hz), 7.52 (1H, d, J=8.0 Hz), 7.60-7.63 (2H, m),7.88-7.91 (2H, m), 7.93 (1H, dd, J=5.0, 1.5 Hz), 10.79 (1H, s), 11.34(1H, s).

Example 23-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2a) N-(4-nitrophenyl)-1H-benzimidazol-2-amine

A mixture of 2-chlorobenzimidazole (10.0 g) and 4-nitroaniline (9.05 g)in NMP (130 mL) was stirred at 120° C. for 3 days. After this time, thereaction mixture was cooled to ambient temperature, diluted with ethylacetate (750 mL) and washed with water (750 mL). The aqueous layer wasextracted with ethyl acetate (750 mL) and the combined organic extractswere washed with water (3×750 mL) then brine (750 mL), dried over sodiumsulfate, and filtered and the filtrate was concentrated under reducedpressure. The residue obtained was triturated with 1:1 ethylacetate/heptane (200 mL) and the solid that formed was collected byfiltration to afford N-(4-nitrophenyl)-1H-benzimidazol-2-amine (4.00 g)as an orange solid.

¹H NMR (500 MHz, DMSO-d₆) δ 7.06-7.08 (2H, m), 7.36-7.37 (1H, m),7.45-7.46 (1H, m), 8.00 (1H, d, J=9.0 Hz), 8.23-8.25 (2H, m), 10.43 (1H,brs), 11.31 (1H, brs).

2b) 1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole

A mixture of N-(4-nitrophenyl)-1H-benzimidazol-2-amine (1.00 g) in DMF(20 ml) at ambient temperature was treated with a 60% dispersion ofsodium hydride in mineral oil (393 mg) then stirred for 5 min. Themixture was treated with a solution of 1,2-dibromoethane (738 mg) in DMF(1 ml) then stirred at ambient temperature for 1 h. After this time, thereaction mixture was quenched with saturated aqueous ammonium chloride(10 mL), diluted with water (80 mL) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with 5% aqueouslithium chloride (2×50 mL) then brine (50 mL), dried over sodiumsulfate, and filtered and the filtrate was concentrated under reducedpressure. The residue obtained was purified by chromatography (silica,heptane to 1:1 ethyl acetate/heptane) to afford1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (63 mg) asa yellow solid.

MS (ESI+): [M+H]⁺ 281.

2c) 4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)aniline

Same procedure of example 1c) with1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (61 mg)gave 4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)aniline (55 mg)as an off-white solid.

MS (ESI+): [M+H]⁺ 251.

2d)N-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-3-nitropyridin-2-amine

A mixture of 4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)aniline(55 mg) and 2-chloro-3-nitropyridine (35 mg) in NMP (3 mL) was stirredat 140° C. overnight. After this time, the reaction mixture was cooledto ambient temperature, diluted with water (50 mL) and extracted withethyl acetate (2×75 mL). The combined organic layers were washed withwater (50 mL) then brine (50 mL), dried over sodium sulfate, andfiltered and the filtrate was concentrated under reduced pressure. Theresidue obtained was purified by chromatography (silica, methylenechloride to 1:9 ethyl acetate/methylene chloride) to affordN-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-3-nitropyridin-2-amine(34 mg) as a dark brown solid.

MS (ESI+): [M+H]⁺ 373.

2e)N²-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]pyridine-2,3-diamine

Same procedure of example 1c) withN-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-3-nitropyridin-2-amine(34 mg) gaveN²-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]pyridine-2,3-diamine(20 mg) as a yellow solid.

MS (ESI+): [M+H]⁺ 343.

2f)3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture ofN²-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]pyridine-2,3-diamine(20 mg) and 1,1′-carbonyldiimidazole (19 mg) in THF (5 mL) was stirredat ambient temperature overnight. After this time, the solids thatformed were collected by filtration to afford3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(12 mg) as off-white crystals.

MS (ESI+): [M+H]⁺ 369.

¹H NMR (500 MHz, DMSO-d₆) δ 4.38-4.41 (2H, m), 4.59-4.63 (2H, m),7.06-7.10 (3H, m), 7.29-7.31 (1H, m), 7.39 (1H, dd, J=7.5, 1.0 Hz),7.43-7.45 (1H, m), 7.65 (2H, d, J=9.0 Hz), 7.93-7.95 (3H, m), 11.34 (1H,brs).

Example 33-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(57 mg) and methyl iodide (0.012 mL) in DMF (2.0 mL) was added sodiumhydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at0° C. for 1 h, and then added H₂O. The precipitate was collected andwashed with MeOH to give3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(43 mg) as white powder.

MS (ESI+): [M+H]⁺ 383.0.

¹H NMR (300 MHz, DMSO-d₆) δ 3.44 (3H, s), 4.33-4.46 (2H, m), 4.53-4.71(2H, m), 7.01-7.12 (2H, m), 7.13-7.22 (1H, m), 7.24-7.35 (1H, m),7.39-7.50 (1H, m), 7.55-7.74 (3H, m), 7.82-8.15 (3H, m).

Example 41-[4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

4a) 1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

A mixture of N-(4-nitrophenyl)-1H-benzimidazol-2-amine (947 mg) andN,N-diisopropylethylamine (1.45 g) in THF (10 mL) at −78° C. was treateddropwise with a solution of bromoacetyl bromide (826 mg) in THF (2.0 mL)then the resulting mixture was allowed to warm to ambient temperatureovernight. After this time, the reaction mixture was diluted with water(50 mL) and extracted with ethyl acetate (2×100 ml). The organic layerswere washed with brine (50 ml), dried over sodium sulfate, and filteredand the filtrate was concentrated under reduced pressure. The residueobtained was purified by chromatography (silica, heptane to 2:3 ethylacetate/heptane) to afford1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (92mg) as a yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 4.84 (2H, s), 7.31 (1H, d, J=7.8 Hz), 7.40(1H, td, J=7.8, 1.2 Hz), 7.63 (1H, d, J=9.6 Hz), 7.81 (1H, d, J=7.5 Hz),7.91 (2H, d, J=9.3 Hz), 8.36 (2H, d, J=9.0 Hz).

4b) 1-(4-aminophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

Same procedure of example 1c) with1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (92mg) gave1-(4-aminophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (82mg) as a yellow solid.

MS (ESI+): [M+H]⁺ 265.

4c)1-{4-[(3-nitropyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

Same procedure of example 2d) with1-(4-aminophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (82mg) gave1-{4-[(3-nitropyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one(7 mg) as a yellow solid.

MS (ESI+): [M+H]⁺ 387.

4d)1-{4-[(3-aminopyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

Same procedure of example 1c) with1-{4-[(3-nitropyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one(7 mg) gave1-{4-[(3-aminopyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one(7 mg) as a yellow solid.

MS (ESI+): [M+H]⁺ 357.

4e)1-[4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one

Same procedure of example 2f) with1-{4-[(3-aminopyridin-2-yl)amino]phenyl}-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one(7 mg) gave1-[4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one(4 mg) as yellow crystals.

MS (ESI+): [M+H]⁺ 383.

¹H NMR (500 MHz, CDCl₃) δ 4.80 (2H, s), 7.08 (1H, dd, J=8.0, 5.5 Hz),7.33-7.36 (3H, m), 7.59 (1H, d, J=8.0 Hz), 7.78 (1H, d, J=8.0 Hz),7.81-7.83 (3H, m), 7.92 (2H, d, J=9.5 Hz), 8.09 (1H, dd, J=5.0, 1.0 Hz).

Example 51-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

5a) 1-(4-nitrophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A mixture of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (431 mg),1-bromo-4-nitrobenzene (778 mg), copper(I) iodide (122 mg),N¹,N²-dimethylethane-1,2-diamine (113 mg) and potassium iodide (1.36 g)in 1,4-dioxane (10 ml) was sparged with argon for 5 min then heatedovernight at 95° C. After this time, the reaction mixture was cooled toambient temperature, diluted with ethyl acetate (100 ml), filteredthrough diatomaceous earth and the filtrate was concentrated underreduced pressure. The residue obtained was purified by chromatography(silica, heptane to 1:1 ethyl acetate/heptane) to afford1-(4-nitrophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (207 mg) asa white solid.

MS (ESI+): [M+H]⁺ 256.

5b) 1-(4-aminophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Same procedure of example 1c) with1-(4-nitrophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (145 mg)gave 1-(4-aminophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120mg) as a yellow solid.

MS (ESI+): [M+H]⁺ 226.

5c)1-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Same procedure of example 1a) with1-(4-aminophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 mg)and 2-chlorobenzo[d]oxazole (98 mg) gave1-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(126 mg) as yellow crystals.

MS (ESI+): [M+H]⁺ 343.

¹H NMR (500 MHz, DMSO-d₆) δ 3.80 (2H, s), 7.08 (1H, dd, J=7.5, 5.5 Hz),7.15 (1H, td, J=8.0, 1.5 Hz), 7.24 (1H, td, J=7.5, 1.0 Hz), 7.45-7.49(3H, m), 7.52 (1H, d, J=8.0 Hz), 7.70 (1H, dd, J=7.0, 1.0 Hz), 7.87 (2H,d, J=9.0 Hz), 8.08-8.09 (1H, m), 10.79 (1H, brs).

Example 63-[4-(1,3-benzoxazol-2-ylamino)phenyl][1,3]oxazolo[4,5-b]pyridin-2(3H)-one

6a) 3-(4-nitrophenyl) [1,3]oxazolo[4,5-b]pyridin-2(3H)-one

A solution of oxazolo[4,5-b]pyridin-2(3H)-one (200 mg) in DMF (3.5 mL)was treated with a 60% dispersion of sodium hydride in mineral oil (62mg) and the resulting mixture stirred at ambient temperature for 5 min.The mixture was treated with 1-fluoro-4-nitrobenzene (248 mg) thenstirred at 100° C. for 17 h. After this time, the reaction mixture wascooled to ambient temperature, diluted with ethyl acetate (100 ml),washed with water (2×50 ml), 5% aqueous lithium chloride (50 mL) thenbrine (50 mL), dried over sodium sulfate, and filtered and the filtratewas concentrated under reduced pressure. The residue obtained waspurified by chromatography (silica, heptane to 1:1 ethylacetate/heptane) to afford 3-(4-nitrophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (73 mg) as a yellow solid.

MS (ESI+): [M+H]⁺ 258.

6b) 3-(4-aminophenyl) [1,3]oxazolo[4,5-b]pyridin-2(3H)-one

Same procedure of example 1c) with3-(4-nitrophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (70 mg) gave3-(4-aminophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (55 mg) as anoff-white solid.

MS (ESI+): [M+H]⁺ 228.

6c)3-[4-(1,3-benzoxazol-2-ylamino)phenyl][1,3]oxazolo[4,5-b]pyridin-2(3H)-one

Same procedure of example 1a) with 3-(4-aminophenyl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (50 mg) and 2-chlorobenzo[d]oxazole(40 mg) gave3-[4-(1,3-benzoxazol-2-ylamino)phenyl][1,3]oxazolo[4,5-b]pyridin-2(3H)-one(58 mg) as brown crystals.

MS (ESI+): [M+H]⁺ 345.

¹H NMR (500 MHz, DMSO-d₆) δ 7.15-7.18 (1H, m), 7.23-7.27 (2H, m), 7.49(1H, dd, J=7.5, 0.5 Hz), 7.52 (1H, d, J=8.0 Hz), 7.68-7.71 (2H, m), 7.81(1H, dd, J=8.0, 1.5 Hz), 7.92-7.95 (2H, m), 8.11 (1H, dd, J=5.5, 1.5Hz), 10.88 (1H, s).

Example 73-[4-(1H-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

7a) N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine

A mixture of 2-chloro-3-nitropyridine (2.0 g), 4-(benzyloxy)anilinehydrochloride (3.6 g), and cesium carbonate (12.3 g) in NMP (50 mL) washeated at 100° C. for 5 h. After cooling to rt, the mixture waspartitioned between AcOEt and H₂O. The organic layer was washed withbrine, dried over Na₂SO₄ and evaporated. The residue was purified bycolumn chromatography (SiO₂, hexane/AcOEt=1/1) to giveN-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (3.04 g) as a brownsolid.

MS (ESI+): [M+H]⁺ 322.0.

7b) N²-[4-(benzyloxy)phenyl]pyridine-2,3-diamine

A mixture of N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (1.5 g), Fe(2.6 g), and CaCl₂ (260 mg) in EtOH (30 mL) and H₂O (6.0 mL) was heatedat 100° C. for 6 h. After cooling to rt, the precipitate was removed byCelite, and the filtrate was concentrated. The residue was partitionedbetween AcOEt and sat.NaHCO₃aq. The organic layer was washed with brine,dried over Na₂SO₄ and evaporated. The residue was purified by columnchromatography (SiO₂, hexane/AcOEt=3/2 to 1/1). The is obtained solidwas rinsed with ^(i)Pr₂O-hexane to giveN²-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g) as a pale pinksolid.

MS (ESI+): [M+H]⁺ 292.1.

7c) 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of N²-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g), CDI(668 mg), and DBU (1.2 ml) in THF (25 mL) was heated at 60° C.overnight. After cooling to rt, the mixture was partitioned betweenAcOEt and H₂O. The organic layer was washed with brine, dried overNa₂SO₄ and evaporated. The residue was purified by column chromatography(SiO₂, hexane/AcOEt=97/3 to 9/1) to give3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (993mg) as a pale brown solid.

MS (ESI+): [M+H]⁺ 318.0.

7d) 3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (500mg) and Pd—C (100 mg) in MeOH (30 mL) was stirred at room temperaturefor 5.5 h. The mixture was filtered by Celite, and the filtrate wasconcentrated. The resulting solid was rinsed with ¹Pr₂O to give3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 mg)as a pale brown solid.

7e)3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 mg),2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (507 mg)and cesium carbonate (1.17 g) in DMF (10 mL) was heated at 100° C. for 4h. After cooling to rt, the mixture was partitioned between AcOEt andH₂O. The organic layer was washed with brine, dried over Na₂SO₄ andevaporated. The residue was purified by column chromatography (SiO₂,hexane/AcOEt=1/1 to 0/1) to give3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(560 mg) as white crystals.

MS (ESI+): [M+H]⁺ 474.0.

7f)3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg), 1 M TBAF in THF (6.3 mL), and TMEDA in THF (20 ml) was heatedat 50° C. for 24 h. After cooling to rt, the mixture was partitionedbetween AcOEt and H₂O. The organic layer was washed with brine, driedover Na₂SO₄ and evaporated. The residue was purified by columnchromatography (SiO₂, hexane/AcOEt=1/3 then AcOEt/MeOH=95/5). Theobtained product was recrystallized from MeOH-iPr₂O to give3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(75 mg) as white crystals.

MS (ESI+): [M+H]⁺ 343.9.

¹H NMR (300 MHz, DMSO-d₆) δ 7.11 (3H, dd, J=5.7, 3.8 Hz), 7.32-7.47 (3H,m), 7.54 (2H, d, J=8.0 Hz), 7.74 (2H, d, J=8.3 Hz), 7.95 (1H, d, J=4.9Hz), 12.04 (2H, brs).

Example 83-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onehydrochloride

2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g)was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.4 g) and sodium hydride (0.263 g) in DMF(dry) (10 mL) at roomtemperature. The mixture was heated at 200° C. for 1 h under microwaveirradiation. The reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography (NH silicagel, eluted with 5%-50% EtOAc in hexane) to give1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.60 g) as a colorless solid. A mixture of1-ethyl-3-{4-[(1-{([2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h.After cooling to room temperature, the solvent was removed in vacuo. Theresidue was recrystallized from EtOH-ether to give3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onehydrochloride (154 mg).

MS (ESI+): [M+H]⁺ 372.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.43 (3H, m), 3.78-4.15 (2H, m),7.12-8.06 (10H, m), 8.62 (2H, brs).

Example 91-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onedihydrochloride

9a) 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A mixture of 4-(benzyloxy)aniline hydrochloride (2.21 g),4-methylbenzenesulfonic acid hydrate (0.178 g), and(2-chloropyridin-3-yl)acetic acid (Journal of Medicinal Chemistry, 1990,33, 2697-2706.) (1.61 g) in 1-pentanol (15 mL) was stirred at 140° C.for 24 h. After cooling to room temperature, the mixture was added toSiO₂, and the mixture was concentrated and purified by columnchromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.39g) as a pale yellow solid.

MS (ESI+): [M+H]⁺ 317.0.

9b)1-[4-(benzyloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A mixture of1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (350mg), iodomethane (0.145 mL), and sodium hydride (49 mg) (60% in mineraloil) in DMF (5 mL) was stirred at 0° C. to room temperature overnight.The mixture was quenched with water at room temperature and extractedwith EtOAc. The organic layer was separated, washed with brine, driedover MgSO₄ and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give1-[4-(benzyloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(198 mg) as an orange solid.

MS (ESI+): [M+H]⁺ 345.4.

9c)1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Same procedure of example 1c) with1-[4-(benzyloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(198 mg) gave1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(139 mg) as a white solid.

MS (ESI+): [M+H]⁺ 255.4.

9d)3,3-dimethyl-1-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Same procedure of example 7e) with1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(139 mg) and2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (155 mg)gave3,3-dimethyl-1-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(258 mg) as white crystals.

MS (ESI+): [M+H]⁺ 501.1.

9e)1-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onedihydrochloride

A mixture of3,3-dimethyl-1-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(258 mg) and 2N HCl in EtOH (5 mL) in EtOH (5 mL) was stirred at 60° C.for 10 h. After cooling to room temperature, the solvent was removed.The residue was recrystallized from EtOH-AcOEt to give1-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onedihydrochloride (152 mg).

MS (ESI+): [M+H]⁺ 371.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (6H, s), 7.12-7.23 (3H, m), 7.38-7.48(2H, m), 7.49-7.72 (4H, m), 7.87 (1H, dd, J=7.4, 1.7 Hz), 8.13 (1H, dd,J=5.3, 1.9 Hz), 8.67 (3H, brs).

Example 103-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

10a)3-[4-(benzyloxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[2-(Chloromethoxy)ethyl](trimethyl)silane (1.673 mL) was added to asolution of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0g) and sodium hydride (0.504 g) (60% in mineral oil) in DMF (5.0 mL) at0° C. The mixture was stirred at room temperature under a dry atmosphere(CaCl₂ tube) for 1 h. After the reaction, the reaction mixture wasdiluted with MeOH and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, eluted with 0%-100% EtOAc in hexane)to give3-[4-(benzyloxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.75 g) as a white solid.

MS (ESI+): [M+H]⁺ 448.1

10b)3-(4-hydroxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Same procedure of example 7d) with3-[4-(benzyloxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.82 g) gave3-(4-hydroxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.23 g) as a white solid.

MS (ESI+): [M+H]⁺ 358.4.

10c)4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyltrifluoromethanesulfonate

N-Phenylbis(trifluoromethanesulfonimide) (4.46 g) was added to asolution of3-(4-hydroxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.23 g) and triethylamine (8.69 mL) in THF (20 mL) at room temperature.The mixture was stirred at 70° C. under a dry atmosphere (CaCl₂ tube)for 3 h. The mixture was neutralized with sat.NaHCO₃aq. at 0° C. andextracted with EtOAc. The organic layer was separated, washed with waterand brine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 0%-30% EtOAcin hexane) to give4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyltrifluoromethanesulfonate (2.90 g) as tan oil.

MS (ESI+): [M+H]⁺ 490.3.

10d)3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyltrifluoromethanesulfonate (2.6 g),4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 mL), triethylamine (2.23mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.218 g) and THF (21.2 mL) was heated at 100° C.for 3 h under microwave irradiation. The mixture was concentrated invacuo. The residue was purified by column chromatography (silica gel,eluted with 0%-30% EtOAc in hexane) to give3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.5 g) as dark yellow oil.

MS (ESI+): [M+H]⁺ 468.2.

10e)3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Benzyl chloride (1.527 mL) was added to a solution of4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g)in DMF (10 mL) at 0° C. The mixture was stirred at room temperatureunder a dry atmosphere for 1 h. The reaction mixture was diluted withMeOH and concentrated in vacuo. The residue was purified by columnchromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) togive 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil.The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg),3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(700 mg), Pd(Ph₃P)₄ (87 mg), sodium carbonate (476 mg) and THF (18mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwaveirradiation. The mixture was poured into water at room temperature andextracted with EtOAc. The organic layer was separated, washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 10%-50% EtOAcin hexane) to give3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(450 mg) as white crystals.

MS (ESI+): [M+H]⁺ 562.4.

Example 113-(4-quinolin-8-ylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyltrifluoromethanesulfonate (500 mg), 8-quinolineboronic acid (265 mg),Pd(Ph₃P)₄ (35.4 mg), 2 M Na₂CO₃ (1.02 mL) and CH₃CN (10 mL) was heatedat 150° C. for 20 min under microwave irradiation. The mixture wasdiluted with sat.NaHCO₃aq. at 0° C. and extracted with EtOAc. Theorganic layer was separated, washed with water and brine, dried overMgSO₄ and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give3-(4-quinolin-8-ylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(410 mg) as white crystals.

MS (ESI+): [M+H]⁺ 469.1.

Example 121-Ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

12a) 1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine

To a stirred solution of 1H-pyrazolo[3,4-b]pyridine (300 mg) in DMF (3.0mL) was added sodium hydride (101 mg) (60% in mineral oil) withice-cooling. The mixture was stirred at room temperature for 30 min, andthen 1-fluoro-4-nitrobenzene (355 mg) was added. After stirring at roomtemperature for 2 h, the mixture was warmed up to 50° C. The mixture wasstirred at 50° C. for 12 h. Cesium carbonate (821 mg) was added and themixture was stirred at 100° C. for 12 h, and treated with water andAcOEt. The insoluble material was filtered off. The organic layer wasseparated and the aqueous layer was extracted with AcOEt. The organiclayer was combined, dried over MgSO₄ and concentrated in vacuo. Theresidue was used for the next reaction.

12b) 4-(1H-pyrazolo[3,4-b]pyridin-1-yl)aniline

Same procedure of example 1c) with1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine obtained from example 12a)gave 4-(1H-pyrazolo[3,4-b]pyridin-1-yl)aniline (50 mg).

MS (ESI+): [M+H]⁺ 211.1.

12c)3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (120 mg),Pd₂(dba)₃ (21.8 mg), Xantphos (27.5 mg), and sodium tert-butoxide (34.3mg) in 2-propanol (8.0 mL) and toluene (2.0 mL) was stirred at 90° C.for 16 h, treated with water and extracted with EtOAc. The organic layerwas separated, dried over MgSO₄ and concentrated in vacuo. The residuewas suspended in DMSO/CH₃CN and the insoluble material was collected byfiltration to give3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(40 mg). The filtrate was concentrated and chromatographed on silica geleluting with AcOEt/Hexane=2/1. Removal of solvent gave second crop (10mg).

MS (ESI+): [M+H]⁺ 329.0.

12d)1-Ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(50 mg) and iodoethane (10.5 μl) was stirred at 50° C. for 30 min,treated with water and extracted with AcOEt. The organic layer was driedover MgSO₄ and concentrated in vacuo. The residue was chromatographed onsilica gel eluting with Hexane/AcOEt=2/1-1/2. The product wascrystallized from AcOEt/hexane to give1-ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(13 mg).

MS (ESI+): [M+H]⁺ 357.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.2 Hz), 4.00 (2H, q, J=7.2Hz), 7.20 (1H, dd, J=7.7, 5.1 Hz), 7.35-7.48 (1H, m), 7.64-7.77 (1H, m),7.83-7.97 (2H, m), 7.97-8.07 (1H, m), 8.39-8.50 (3H, m), 8.53 (1H, s),8.73 (1H, dd, J=4.5, 1.5 Hz).

Example 133-[1-(1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

13a) tert-butyl 5-nitro-2,3-dihydro-1H-indole-1-carboxylate

To a stirred mixture of 5-nitroindoline (5.0 g) and Boc₂O (7.07 mL) inTHF (100 mL) was added DMAP (0.5 g) at room temperature. The mixture wasstirred at 60° C. for 3 h. The mixture was quenched with water, treatedwith sat. NaHCO₃aq. and extracted with EtOAc. The organic layer wasdried over MgSO₄ and concentrated in vacuo. The residue was used for thenext reaction without further purification.

13b) tert-butyl 5-amino-2,3-dihydro-1H-indole-1-carboxylate

Under H₂ atmosphere, a mixture of tert-butyl5-nitro-2,3-dihydro-1H-indole-1-carboxylate, obtained from example 13a),and 10% Pd—C (5 g) in EtOH (100 mL) was stirred at room temperature for12 h, filtered and concentrated in vacuo to give tert-butyl5-amino-2,3-dihydro-1H-indole-1-carboxylate (6.80 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.47 (9H, s), 2.91 (2H, t, J=8.5 Hz), 3.79(2H, t, J=8.5 Hz), 4.73 (2H, brs), 6.33 (1H, dd, J=8.7, 2.3 Hz), 6.43(1H, s), 6.95-7.53 (1H, m).

13c) tert-butyl5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate

A mixture of tert-butyl 5-amino-2,3-dihydro-1H-indole-1-carboxylate(4.10 g), tert-butyl 2-chloropyridin-3-ylcarbamate (4.20 g), Pd₂(dba)₃(0.48 g), Xantphos (0.608 g), sodium tert-butoxide (2.52 g) in2-propanol (64 mL) and toluene (12 mL) was stirred at 90° C. for 40 h,and treated with water and extracted with EtOAc. The organic layer wasdried over MgSO₄ and concentrated in vacuo. The residue was suspended inCH₃CN and the precipitate was collected by filtration to give tert-butyl5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate(1.64 g). The filtrate was evaporated and then the residue waschromatographed on silica gel eluting with AcOEt/Hexane=2/1 to affordsecond crop (1.4 g).

MS (ESI+): [M+H]⁺ 353.3.

13d) tert-butyl5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate

A mixture of tert-butyl5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate(900 mg), ethyl iodide (418 mg) and cesium carbonate (1.25 g) in DMF (10mL) was stirred at 50° C. for 12 h, treated with water and extractedwith EtOAc. The organic layer was dried over MgSO₄ and concentrated invacuo. The residue was chromatographed on silica gel eluting withAcOEt/Hexane to give tert-butyl5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate(830 mg) as an amorphous solid.

MS (ESI+): [M+H]⁺ 381.2.

13e)3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred solution of tert-butyl5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate(100 mg) in EtOAc (2 ml) was added 4N HCl in AcOEt solution (2.0 mL).The mixture was stirred at 50° C. for 2 h and evaporated. The residuewas treated with sat.NaHCO₃aq. and extracted with AcOEt. The organiclayer was dried over MgSO₄ and concentrated in vacuo to give3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.This residue was used for the next reaction.

MS (ESI+): [M+H]⁺ 281.2.

13f)3-[1-(1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneobtained from example 13e) and2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (108 mg)in NMP (2.0 ml) was stirred at 120° C. for 12 h, treated withsat.NaHCO₃aq. and extracted with AcOEt. The organic layer was dried overMgSO₄ and concentrated in vacuo. The residue was purified by preparativeHPLC and crystallized from AcOEt/Hexane to give3-[1-(1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(12 mg).

MS (ESI+): [M+H]⁺ 397.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (3H, t, J=7.2 Hz), 3.33-3.39 (2H, m),3.92-4.03 (2H, m), 4.24 (2H, t, J=8.7 Hz), 6.96-7.20 (3H, m), 7.30-7.36(1H, m), 7.38-7.48 (3H, m), 7.56-7.70 (1H, m), 7.91-8.03 (1H, m), 8.36(1H, d, J=8.7 Hz), 11.72 (1H, s).

Example 149-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one

14a) 4-chloro-5-nitropyrimidine

The mixture of 5-nitropyrimidin-4-ol (1.04 g) and phosphorus oxychloride(5.66 g) in acetonitrile (10 mL) was stirred at reflux for 2 h. Afterthis time, the reaction mixture was cooled to ambient temperature,diluted with ethyl acetate (50 mL), and filtered and the filtrate wasconcentrated under reduced pressure. The residue obtained was dilutedwith ethyl acetate (100 mL), washed with saturated aqueous sodiumbicarbonate (50 mL) then brine (50 mL), and filtered and the filtratewas concentrated under reduced pressure. The residue obtained waspurified by chromatography (silica, heptane to 1:3 ethylacetate/heptane) to afford 4-chloro-5-nitropyrimidine (383 mg, 33%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃) δ 9.19 (s, 1H), 9.25 (s, 1H).

14b) N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine

A mixture of 4-chloro-5-nitropyrimidine (380 mg) and benzene-1,4-diamine(257 mg) in N-methylpyrrolidone (5 mL) was stirred overnight at ambienttemperature. After this time, the reaction mixture was diluted withwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with saturated sodium bicarbonate (50 mL)then brine (50 mL), dried over sodium sulfate, and filtered and thefiltrate was concentrated under reduced pressure. The residue obtainedwas purified by chromatography (silica, methylene chloride to 3:97methanol/methylene chloride) to affordN-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (260 mg) as a brown oil.

MS (ESI+): [M+H]⁺ 232.

¹H NMR (300 MHz, CDCl₃) δ 3.79 (br s, 2H), 6.74 (d, J=8.7 Hz, 2H), 7.32(d, J=8.4 Hz, 2H), 8.74 (s, 1H), 9.28 (s, 1H), 9.92 (br s, 1H).

14c) N-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine

A mixture of N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (256 mg),2-chloro-1,3-benzoxazole (110 mg) in N-methylpyrrolidone (3 mL) wasstirred at 120° C. for 45 min. After this time, the reaction mixture wascooled to ambient temperature, diluted with water (50 mL) and extractedwith ethyl acetate (100 mL). The organic layer was washed with water (50mL) then brine (50 ml), dried over sodium sulfate, and filtered and thefiltrate was concentrated under reduced pressure. The residue obtainedwas purified by chromatography (silica, methylene chloride to 1:3 ethylacetate/methylene chloride) to affordN-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (107mg) as a red solid.

MS (ESI+): [M+H]⁺ 349.

14d) N⁴-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine

A mixture ofN-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (54mg) and 5% palladium on carbon (22 mg, 50% water by weight) in methanol(5 mL) was stirred under an atmosphere of hydrogen (balloon) for 1 h.After this time, the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure to affordN⁴-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (49 mg) asa brown solid.

MS (ESI+): [M+H]⁺ 319.

¹H NMR (300 MHz, DMSO-d₆) δ 5.14 (br s, 2H), 7.11 (td, J=7.5, 1.2 Hz,1H), 7.21 (td, J=7.5, 0.9 Hz, 1H), 7.43 (dd, J=8.4, 0.6 Hz, 1H), 7.48(d, J=7.5 Hz, 1H), 7.70 (s, 4H), 7.76 (s, 1H), 8.02 (s, 1H), 8.28 (br s,1H), 10.52 (br s, 1H).

14e) 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one

A mixture ofN⁴-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (55 mg)and bis(2,5-dioxopyrrolidin-1-yl) carbonate (53 mg) in DMF (5 mL) wasstirred overnight at 80° C. then at 95° C. for 3 h. After this time, thereaction mixture was cooled to ambient temperature, diluted with water(50 mL) and extracted with ethyl acetate (100 mL). The organic layer waswashed with water (50 mL), 5% aqueous lithium chloride (50 mL) thenbrine (50 mL), dried over sodium sulfate, and filtered and the filtratewas concentrated under reduced pressure. The residue obtained waspurified by chromatography (silica, methylene chloride to 1:9methanol/methylene chloride), solvent exchanged with acetonitrile andfreeze dried from acetonitrile/water to afford9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one (19mg) as off-white crystals.

MS (ESI+): [M+H]⁺ 345.

¹H NMR (500 MHz, DMSO-d₆) δ 7.16 (td, J=7.5, 1.0 Hz, 1H), 7.25 (td,J=7.5, 1.0 Hz, 1H), 7.48 (d, J=7.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.62(d, J=9.0 Hz, 2H), 7.91 (d, J=9.0 Hz, 2H), 8.33 (s, 1H), 8.56 (s, 1H),10.84 (br s, 1H), 11.62 (br s, 1H).

Example 191-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-1-methyl-1H-benzimidazole (500 mg) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(789 mg) and NaH (132 mg) in DMF (10 mL) at room temperature. Themixture was heated at 150° C. for 1 h under microwave irradiation. Thereaction mixture was diluted with MeOH and concentrated in vacuo. Theresidue was purified by column chromatography (NH silica gel, elutedwith 0%-50% EtOAc in hexane) to give1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(950 mg) as white crystals.

MS (API+): [M+H]⁺ 386.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.45 (3H, m), 3.76 (3H, s), 3.92-4.06(2H, m), 7.08-7.27 (3H, m), 7.39-7.53 (2H, m), 7.56-7.64 (2H, m),7.65-7.73 (1H, m), 7.73-7.84 (2H, m), 7.96-8.08 (1H, m).

Anal. Calcd for

C₂₂H₁₉N₅O₂: C, 68.56; H, 4.97; N, 18.17. Found: C, 68.40; H, 5.00; N,17.94.

Mp: 184-186° C.

Example 243-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(150 mg) and ethyl iodide (0.1 mL) in DMF (4.0 mL) was added sodiumhydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at0° C. for 1 h, and then H₂O was added. The precipitate was collected andwashed with MeOH to give3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(23 mg) as white powder.

MS (API+): [M+H]⁺ 397.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2 Hz), 3.98 (2H, q, J=7.2Hz), 4.34-4.46 (2H, m), 4.55-4.67 (2H, m), 7.03-7.11 (2H, m), 7.13-7.21(1H, m), 7.27-7.35 (1H, m), 7.40-7.49 (1H, m), 7.62-7.71 (3H, m),7.90-8.01 (3H, m).

Example 311-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

31a) 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (12.5 g),4-benzyloxyaniline hydrochloride (19.3 g),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd₂(dba)₃ (2.0g) and sodium tert-butoxide (12.6 g) in toluene (160 mL) -2-propanol(40.0 mL) was stirred at 100° C. under Ar overnight. The reactionmixture was concentrated in vacuo. The residue was purified by columnchromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12g) as a light brown solid.

MS (API+): [M+H]⁺ 318.1.

¹H NMR (300 MHz, DMSO-d₆) δ 5.18 (2H, s), 7.02-7.22 (3H, m), 7.29-7.59(8H, m), 7.86-7.94 (1H, m), 11.11-11.64 (1H, m).

31b)3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.50g), sodium hydride (380 mg) and iodoethane (1.60 mL) in DMF (40 mL) wasstirred at 20° C. under a dry atmosphere (CaCl₂ tube) for 1 h. Themixture was concentrated under reduced pressure. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-30%EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.70 g) as a colorless solid.

MS (API+): [M+H]⁺ 346.4.

¹H NMR (300 MHz, CDCl₃) δ 1.40 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2Hz), 5.11 (2H, s), 7.01-7.17 (3H, m), 7.22-7.29 (1H, m), 7.29-7.49 (5H,m), 7.53-7.61 (2H, m), 8.00-8.09 (1H, m).

31c)1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.70 g) and 10% palladium-carbon (0.83 g) in EtOH (250 mL) washydrogenated under balloon pressure at room temperature for 3 h. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to give1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.42 g) as a white solid.

MS (API+): [M+H]⁺ 256.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (3H, t, J=7.2 Hz), 3.95 (2H, q, J=7.2Hz), 6.84-6.95 (2H, m), 7.08-7.18 (1H, m), 7.32-7.40 (2H, m), 7.57-7.67(1H, m), 7.89-7.99 (1H, m), 9.67-9.79 (1H, m).

31d) ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate

n-Butyllithium (1.6M in hexane, 45.1 mL) was added to a solution of2-chloroimidazo[1,2-a]pyridine (10 g) in THF (120 mL) at −78° C. Afterstirring for 30 min, ethyl chlorocarbonate (7.82 g) in THF (10 ml) wasadded to the mixture at the same temperature and stirred for 1 h andthen 10 h at room temperature. The mixture was quenched with water, andextracted with ethyl acetate, and the extract was washed with brine, anddried over magnesium sulfate. The residue was purified by columnchromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to giveethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (13.20 g) as anoff-white solid.

MS (API+): [M+H]⁺ 225.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (3H, m), 4.40 (2H, m), 7.31 (1H, s),7.66 (1H, s), 7.72-7.86 (1H, m), 9.17-9.32 (1 H, m).

31e)1-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (220mg), NaH (70 mg) and1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(255 mg) in DMF (2 mL) was stirred at 100° C. under a dry atmosphere(CaCl₂ tube) for 1 h. The mixture was diluted with MeOH and concentratedunder reduced pressure. The residue was purified by columnchromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) togive1-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(40 mg) as white crystals.

MS (API+): [M+H]⁺ 372.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.36 (3H, m), 3.92-4.06 (2H, m),6.90-7.00 (1H, m), 7.11-7.23 (1H, m), 7.23-7.41 (3H, m), 7.44-7.54 (1H,m), 7.60-7.75 (4H, m), 7.94-8.10 (1H, m), 8.47-8.60 (1H, m).

Example 391-ethyl-3-(4-{[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

39a) ethyl{2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate

Ethyl bromoacetate (0.240 mL) was added to a solution of3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(400 mg) and sodium hydride (86 mg) in DMF (2 mL) at room temperature.The mixture was stirred at room temperature under a dry atmosphere(CaCl₂ tube) for 2 h. The reaction mixture was diluted with MeOH (5 mL),and concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, eluted with 0%-50% EtOAc in hexane)to give ethyl{2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate(480 mg) as off-white crystals.

MS (API+): [M+H]⁺ 458.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24 (3H, t, J=7.0 Hz), 1.30 (3H, t, J=7.2Hz), 3.99 (2H, q, J=7.2 Hz), 4.22 (2H, q, J=7.0 Hz), 5.18-5.28 (2H, m),7.11-7.25 (3H, m), 7.42-7.60 (4H, m), 7.65-7.72 (1H, m), 7.74-7.83 (2H,m), 7.96-8.05 (1H, m).

39b)1-ethyl-3-(4-{[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Lithium aluminum hydride (33.2 mg) was added to a solution of ethyl{2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate(200 mg) in THF (4 mL) at 0° C. The mixture was stirred at roomtemperature under a dry atmosphere (CaCl₂ tube) for 30 min. The mixturewas quenched with EtOAc and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 10%-50% EtOAcin hexane) to give1-ethyl-3-(4-{[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) as colorless crystals.

MS (API+): [M+H]⁺ 416.5.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.0 Hz), 3.75-3.88 (2H, m),3.99 (2H, q, J=7.0 Hz), 4.23-4.37 (2H, m), 4.98-5.07 (1H, m), 7.09-7.28(3H, m), 7.39-7.65 (4H, m), 7.65-7.87 (3H, m), 7.95-8.08 (1H, m).

Example 401-ethyl-3-(4-{[1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Bromomethylmagnesium (3M in ether, 1.924 mL) was added to a solution ofethyl{2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate(220 mg) in THF (40 ml) at 0° C. The mixture was stirred at roomtemperature under a dry atmosphere (CaCl₂ tube) for 3 h. The reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, eluted with 0%-50% EtOAcin hexane) to give1-ethyl-3-(4-{[1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(130 mg) as white crystals.

MS (API+): [M+H]⁺ 444.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24 (6H, s), 1.31 (3H, t, J=7.2 Hz), 3.99(2H, q, J=7.2 Hz), 4.11 (2H, s), 4.79 (1H, s), 7.07-7.26 (3H, m),7.37-7.46 (1H, m), 7.50-7.64 (3H, m), 7.65-7.81 (3H, m), 7.96-8.05 (1H,m).

Example 481-ethyl-3-[1-(1-methyl-1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) and2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (101 mg)in NMP (2 ml) was stirred at 120° C. for 10 h, treated with saturatedNaHCO₃ solution and extracted with AcOEt. The organic layer was driedover MgSO₄ and concentrated in vacuo. The residue was dissolved in DMF(2 mL), and then iodomethane (0.022 mL) and Cs₂CO₃ (0.176 g) were added.The mixture was stirred at room temperature for 3 h, treated with waterand extracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was suspended in CH₃CN and theprecipitate was filtered off. The residue was purified by prep. HPLC,and then chromatographed on silica gel eluting with AcOEt/Hexane.Crystallization from AcOEt/Hexane gave the title compound (12 mg).

MS (API+): [M+H]+ 411.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (3H, t, J=7.0 Hz), 3.26 (2H, t, J=8.1Hz), 3.77 (3H, s), 3.96 (2H, q, J=6.8 Hz), 4.20 (2H, t, J=8.5 Hz),7.06-7.25 (4H, m), 7.27-7.36 (1H, m), 7.43-7.54 (3H, m), 7.59-7.71 (1H,m), 7.87-8.05 (1H, m).

Example 623-[4-(1H-benzimidazol-2-yloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onedihydrochloride

62a) tert-butyl{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}carbamate

A mixture of2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (8.7 g),tert-butyl 4-hydroxyphenylcarbamate (6.4 g) and cesium carbonate (20 g)in DMF (60 mL) was stirred at 60° C. for 24 h. After cooling to roomtemperature, to the mixture was added SiO₂, the mixture was evaporated,and then the residue was purified by column chromatography (silica gel,eluted with 0%-50% EtOAc in hexane) to give tert-butyl{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}carbamate(14 g) as brown oil.

MS (API+): [M+H]⁺ 456.2.

62b)4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]aniline

A mixture of tert-butyl{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}carbamate(14 g) and 4N HCl/AcOEt (30 mL) in EtOAc (30 ml) was stirred at roomtemperature overnight. The mixture was neutralized with 1N NaOHaq., andextracted with AcOEt. The organic layer was dried over MgSO₄, andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, eluted with 0%-100% EtOAc in hexane) to give4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]aniline(5.4 g) as an orange solid.

MS (API+): [M+H]⁺ 356.2.

62c) 2-chloro-4-methylpyridin-3-amine

A mixture of 4-methylpyridin-3-amine (0.62 g), 12N hydrogen chloride(3.8 mL) and 30% hydrogen peroxide (0.75 mL) was stirred at 0° C. toroom temperature for 1 h. The mixture was neutralized with K₂CO₃, andthe mixture was extracted with AcOEt. The organic layer was dried overMgSO₄, and concentrated in vacuo to give2-chloro-4-methylpyridin-3-amine (0.75 g) as an orange solid.

MS (API+): [M+H]⁺ 143.1.

62d) tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate

To a mixture of 2-chloro-4-methylpyridin-3-amine (0.75 g) anddi-tert-butyl dicarbonate (1.3 mL) in THF (10 mL) was added dropwisehexamethyldisilazane sodium salt (2M in THF, 6.1 mL) at 0° C. Themixture was stirred at 0° C. to room temperature overnight. The mixturewas neutralized with 1N HClaq., and the mixture was extracted withAcOEt. The organic layer was dried over MgSO₄, and concentrated in vacuoto give tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (1.2 g) asan orange solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.34 (9H, brs), 2.15 (3H, s), 7.23 (1H, d,J=4.9 Hz), 8.05 (1H, d, J=4.9 Hz), 8.79 (1H, brs).

62e)7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of sodium 2-methylpropan-2-olate (0.16 g),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.054 g),tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (0.28 g),4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]aniline(0.41 g) and Pd₂(dba)₃ (0.043 g) in toluene (40 mL) and 2-propanol (10mL) was stirred at 100° C. under N₂ overnight. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, eluted with 0%-100%EtOAc in hexane) to give7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.21 g) as white crystals.

MS (API+): [M+H]⁺ 488.3.

62f)3-[4-(1H-benzimidazol-2-yloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onedihydrochloride

A mixture of7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.053 g) and 2N HCl in EtOH (5.0 mL) was stirred at 60° C. for 10 h.After cooling to room temperature, the solvent was removed. The residuewas recrystallized from EtOH-AcOEt to give3-[4-(1H-benzimidazol-2-yloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onedihydrochloride (0.030 g)

MS (API+): [M+H]⁺ 358.1.

¹H NMR (300 MHz, DMSO-d₆) δ 2.37 (3H, s), 4.57 (3H, brs), 6.97 (1H, d,J=5.3 Hz), 7.15 (2H, dd, J=6.1, 3.4 Hz), 7.40 (2H, dd, J=5.9, 3.2 Hz),7.52-7.62 (2H, m), 7.71-7.80 (2H, m), 7.85 (1H, d, J=5.3 Hz), 11.54 (1H,s).

Example 643-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onedihydrochloride

64a)1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.15 g), iodoethane (0.027 mL) and sodium hydride (0.015 g) (60% inoil) in DMF (4.0 mL) was stirred at room temperature for 4 h. To themixture was added H₂O, and the mixture was extracted with AcOEt. Theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by column chromatography (silica gel, eluted with 0%-50%EtOAc in hexane) to give1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(90 mg) as pale yellow crystals.

MS (API+): [M+H]⁺ 516.3.

64b)3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onedihydrochloride

A mixture of1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.090 g) and 2N HCl in EtOH (5.0 mL) was stirred at 60° C. for 10 h.After cooling to room temperature, the solvent was removed. The residuewas recrystallized from EtOH-AcOEt to give3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onedihydrochloride (0.040 g).

MS (API+): [M+H]⁺ 386.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.2 Hz), 2.61 (3H, s), 4.12(2H, q, J=7.2 Hz), 7.01 (1H, d, J=5.3 Hz), 7.20 (2H, dd, J=5.9, 3.2 Hz),7.40-7.49 (2H, m), 7.58-7.66 (2H, m), 7.72-7.81 (2H, m), 7.87 (1H, d,J=4.9 Hz), 8.12 (3H, brs).

Example 651-Ethyl-3-[4-(1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

65a)3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (10.0 g),4-nitroaniline (8.0 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene(2.53 g), Pd₂(dba)₃ (2 g) and sodium tert-butoxide (12.5 g) in toluene(160 mL)-2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight.The reaction mixture was concentrated in vacuo. The residue was purifiedby column chromatography (silica gel, eluted with 0%-100% EtOAc inhexane) to give3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.0 g) asa light brown solid. A mixture of3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.50 g),sodium hydride (0.400 g) and iodoethane (2.0 mL) in DMF (40 mL) wasstirred at 20° C. under a dry atmosphere (CaCl₂ tube) for 1 h. Themixture was concentrated under reduced pressure. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-30%EtOAc in hexane) to give1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.70 g) as a brown solid. A mixture of1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) washydrogenated under balloon pressure at room temperature for 3 h. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to give3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.00 g) as a brown solid.

MS (API+): [M+H]⁺ 255.1.

65b) 2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole

A mixture of 2-chloro-1H-benzimidazole (6.10 g), bromoacetaldehydediethyl acetal (7.22 mL), EtOH (70 mL), and 8 M NaOH aqueous solution(10 mL) was refluxed for 3 d. The reaction mixture was poured into waterand the mixture was extracted with AcOEt. The extract was washed withbrine, dried over MgSO₄, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography elutingwith hexane/AcOEt (10/1) to give2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole (5.50 g).

MS (API+): [M+H]⁺ 269.1.

¹H NMR (300 MHz, CDCl₃) δ 1.10 (6H, t, J=7.2 Hz), 3.39 (2H, dq, J=9.1,7.2 Hz), 3.72 (2H, dq, J=9.1, 7.2 Hz), 4.29 (2H, d, J=5.7 Hz), 4.72 (1H,t, J=5.7 Hz), 7.23-7.32 (2H, m), 7.39-7.47 (1H, m), 7.64-7.72 (1H, m).

mp 29-31° C.

Anal. Calcd for C₁₃H₁₇ClN₂O₂: C, 58.10; H, 6.38; N, 10.42. Found: C,57.80; H, 6.31; N, 10.47.

65c)1-ethyl-3-[4-(1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of 2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole (860 mg)and 3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(636 mg) was heated at 150° C. for 50 min. The reaction mixture waspartitioned between AcOEt/THF (1/1) and 1 M NaOH aqueous solution. Theorganic layer was separated, washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography eluting with THF and recrystallizedfrom THF to give1-ethyl-3-[4-(1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(311 mg).

MS (API+): [M+H]⁺ 395.3.

¹H NMR (300 MHz, CDCl₃) δ 1.43 (3H, t, J=7.2 Hz), 4.05 (2H, q, J=7.2Hz), 7.10 (1H, dd, J=7.9, 5.3 Hz), 7.17-7.22 (1H, m), 7.29 (1H, dd,J=7.9, 1.5 Hz), 7.32-7.37 (2H, m), 7.44 (1H, d, J=2.6 Hz), 7.62 (1H, d,J=7.6 Hz), 7.80 (1H, d, J=8.3 Hz), 7.91-7.96 (2H, m), 8.08 (1H, dd,J=5.3, 1.5 Hz), 8.15-8.20 (2H, m).

mp 220-221° C.

Anal. Calcd for C₂₃H₁₈N₆O: C, 70.04; H, 4.60; N, 21.31. Found: C, 70.12;H, 4.63; N, 21.39.

Example 661-ethyl-3-[1-(1,3-thiazol-2-yl)-1H-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(75 mg), 2-chlorothiazole (48.0 mg) and Cs₂CO₃ (174 mg) in DMF (3 mL)was stirred at 100° C. for 3 days, treated with saturated NaHCO₃solution, and extracted with AcOEt. The organic layer was separated,dried over MgSO₄ and concentrated in vacuo. The residue was purified byprep. HPLC and crystallized from AcOEt/Hexane to give the title compoundas white crystals (27.0 mg).

MS (API+): [M+H]+ 362.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.2 Hz), 4.00 (2H, q, J=7.2Hz), 6.93 (1H, d, J=3.4 Hz), 7.08-7.22 (1H, m), 7.54-7.64 (2H, m),7.65-7.78 (2H, m), 7.88-8.08 (3H, m), 8.41-8.52 (1H, m).

Example 693-[1-(1H-benzimidazol-2-yl)-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[1-(1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) and manganese dioxide (439 mg) in toluene (8 mL) was stirred at100° C. for 5 h, filtered, treated with water and extracted with AcOEt.The organic layer was dried over MgSO₄ and concentrated in vacuo. Theresidue was chromatographed on silica gel eluting with AcOEt/Hexane.Crystallization from AcOEt/Hexane gave the title compound (28.0 mg).

MS (API+): [M+H]+ 395.2.

Example 701-ethyl-3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

70a) 1-(5-methylpyridin-2-yl)-1H-indazol-5-amine

To a stirred solution of 5-nitro-1H-indazole (500 mg) in DMF (10 mL) wasadded 60% sodium hydride (129 mg) at room temperature. The mixture wasstirred for 30 min, and 5-bromo-2-chloropyridine (649 mg) was added. Themixture was exposed to microwave irradiation at 230° C. for 1 h, treatedwith sat. ammonium chloride solution, and extracted with AcOEt. Theorganic layer was dried over MgSO₄ and concentrated in vacuo. Theresidue was chromatographed on silica gel eluting with AcOEt/Hexane togive a mixture of 1-(5-bromopyridin-2-yl)-5-nitro-1H-indazole and2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole.

To the mixture of 1-(5-bromopyridin-2-yl)-5-nitro-1H-indazole and2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole were added methylboronicacid (141 mg), Pd(Ph₃P)₄ (91 mg), DME (3 mL) and a solution of Cs₂CO₃(766 mg) in H₂O (1 mL), successively. The mixture was exposed tomicrowave irradiation at 140° C. for 1 h, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo to give a mixture of1-(5-methylpyridin-2-yl)-5-nitro-1H-indazole and2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole.

The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-1H-indazole and2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20mL), and 10% Pd/C (250 mg) was added. Under H₂ atmosphere, the mixturewas stirred at room temperature for 12 h, filtered and concentrated invacuo. The residue was chromatographed on silica gel eluting withAcOEt/Hexane to give the title compound as white crystals (76 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (3H, s), 5.06 (2H, s), 6.84 (1H, d,J=1.5 Hz), 6.91 (1H, dd, J=8.9, 2.1 Hz), 7.71-7.87 (2H, m), 8.09 (1H,s), 8.33 (1H, d, J=2.3 Hz), 8.38-8.46 (1H, m).

70b)3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Under argon atmosphere, a mixture of1-(5-methylpyridin-2-yl)-1H-indazol-5-amine (71 mg), tert-butyl2-chloropyridin-3-ylcarbamate (80 mg), Pd₂(dba)₃ (29.0 mg), Xantphos(36.6 mg) and sodium tert-butoxide (33.5 mg) in 2-propanol (2 mL) andtoluene (0.5 mL) was stirred at 90° C. for 24 h, treated with water andextracted with EtOAc. The organic layer was separated, dried over MgSO₄and concentrated in vacuo. The residue was chromatographed on silica geleluting with AcOEt/Hexane to give the title compound as white crystals(70.0 mg).

MS (API+): [M+H]+ 343.3.

70c)1-ethyl-3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(70 mg) and iodoethane (35.1 mg) in DMF (2 mL) was stirred at 50° C. for3 h, treated with water, and extracted with AcOEt. The organic layer wasdried over MgSO₄ and concentrated in vacuo. The residue waschromatographed on silica gel eluting with AcOEt/Hexane. The product wascrystallized from AcOEt/Hexane to give the title compound as whitecrystals (25.0 mg).

MS (API+): [M+H]+ 371.0.

Example 711-ethyl-3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-1H-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

71a) 2-Chloro-3H-imidazo[4,5-b]pyridine

2-(Methylthio)-3H-imidazo[4,5-b]pyridine (3.5 g) was dissolved in conc.HCl (10 mL), and then the mixture was cooled to 0° C. Chlorine gas wasbubbled through the mixture for 2 h in iced bath. The mixture was pouredonto ice, and neutralized to pH 7 with aqueous ammonium solution. Theprecipitate was collected by filtration to give the title compound aswhite crystals (1.0 g).

MS (API+): [M+H]⁺ 154.0.

71b)1-ethyl-3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-1H-indol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Under nitrogen atmosphere, a mixture of3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (60.3 mg) in NMP (4 mL)was stirred at 150° C. for 2 h, treated with water, and extracted withAcOEt. The organic layer was dried over MgSO₄ and concentrated in vacuo.The residue was purified by prep. HPLC. Crystallization from EtOH/H₂O togive the title compound (18.0 mg).

MS (API+): [M+H]⁺ 398.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (3H, t, J=7.0 Hz), 3.36-3.41 (2H, m),3.97 (2H, q, J=7.1 Hz), 4.19-4.34 (2H, m), 6.98-7.10 (1H, m), 7.12-7.20(1H, m), 7.39-7.49 (2H, m), 7.62-7.72 (2H, m), 7.93-8.01 (1H, m),8.02-8.17 (1H, m), 8.41 (1H, d, J=9.1 Hz).

Example 723-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

72a) tert-Butyl5-[1-(1-methylethyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate

A mixture of tert-butyl5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate(1480 mg) and 2-iodopropane (714 mg) in DMF (5 mL) was stirred at 60° C.for 4 h, treated with water, and extracted with AcOEt. The organic layerwas dried over MgSO₄ and concentrated in vacuo. The residue waschromatographed on silica gel eluting with AcOEt/Hexane to give thetitle compound as white crystals (570 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.44-1.60 (15H, m), 3.12 (2H, t, J=8.7 Hz),3.92-4.01 (2H, m), 4.65-4.74 (1H, m), 7.07-7.15 (1H, m), 7.31-7.45 (2H,m), 7.72-7.79 (2H, m), 7.90-7.99 (1H, m).

72b)3-(2,3-dihydro-1H-indol-5-yl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred mixture of tert-butyl5-[1-(1-methylethyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylatein AcOEt/EtOH (1/1, 10 mL) was added 4N HCl in AcOEt (4 mL). The mixturewas stirred at 80° C. for 2 h, evaporated, treated with saturatedNaHCO₃, and extracted with AcOEt. The organic layer was dried over MgSO₄and concentrated in vacuo. The residue was suspended in IPE and thesuspension was collected by filtration to give the title compound aswhite crystals (313 mg).

MS (API+): [M+H]⁺ 295.1.

72c)3-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-(2,3-dihydro-1H-indol-5-yl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(200 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (115 mg) in NMP (4 mL)was stirred at 140° C. for 1.5 h, treated with saturated NaHCO₃, andextracted with AcOEt. The organic layer was dried over MgSO₄, passedthrough celite pad covered with activated carbon and concentrated invacuo. The residue was purified by prep. HPLC. The product wascrystallized from EtOH/hexane to give the title compound (15.0 mg).

MS (API+): [M+H]⁺ 412.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.51 (6H, d, J=7.2 Hz), 3.38-3.45 (2H, m),4.20-4.35 (2H, m), 4.72 (1H, sep, J=7.2 Hz), 6.97-7.17 (2H, m),7.36-7.50 (2H, m), 7.60-7.81 (2H, m), 7.96 (1H, d, J=5.3 Hz), 8.01-8.18(1H, m), 8.34-8.47 (1H, m), 12.20 (1H, brs).

Example 751-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

75a)3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.50g), sodium hydride (0.378 g) and iodoethane (1.60 mL) in DMF (25 mL) wasstirred at 20° C. under a dry atmosphere (CaCl₂ tube) for 1 h. Thereaction mixture was diluted with MeOH (10 mL) and concentrated underreduced pressure. The residue was purified by column chromatography (NHsilica gel, eluted with 0%-30% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.70 g) as a colorless solid.

MS (API+): [M+H]⁺ 346.4.

¹H NMR (300 MHz, CDCl₃) δ 1.40 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2Hz), 5.11 (2H, s), 7.01-7.17 (3H, m), 7.22-7.29 (1H, m), 7.29-7.49 (5H,m), 7.53-7.61 (2H, m), 8.00-8.09 (1H, m).

75b)1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) washydrogenated under balloon pressure at room temperature for 3 h. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to give1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.42 g) as a white solid.

MS (API+): [M+H]⁺ 256.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (3H, t, J=7.2 Hz), 3.95 (2H, q, J=7.2Hz), 6.84-6.95 (2H, m), 7.08-7.18 (1H, m), 7.32-7.40 (2H, m), 7.57-7.67(1H, m), 7.89-7.99 (1H, m), 9.67-9.79 (1H, m).

75c) 1H-imidazo[4,5-b]pyridine-2-thiol

To a solution of pyridine-2,3-diamine (5 g) in EtOH (150 ml) was addedcarbon disulfide (23 mL) at room temperature. The mixture was stirred at40° C. under Ar for 10 h. The mixture was cooled to room temperature.The resulting white solid was filtered and washed with ether to give1H-imidazo[4,5-b]pyridine-2-thiol (5.61 g).

MS (API+): [M+H]⁺ 152.2.

¹H NMR (300 MHz, DMSO-d₆) δ 7.13 (1H, m), 7.47 (1H, d, J=6.8 Hz),7.97-8.36 (1H, m), 12.72 (1H, br. s.), 13.13 (1H, br. s.).

75d) 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine

To a solution of 1H-imidazo[4,5-b]pyridine-2-thiol (2 g) in acetone (30mL) were added MeI (0.910 ml) and K₂CO₃ (5.48 g) at room temperature.After stirring for 10 h, the mixture was concentrated under reducedpressure. The residue was purified by column chromatography (NH-silicagel, eluted with 10%-100% EtOAc in hexane) to give2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (1.0 g) as a white solid.

MS (API+): [M+H]⁺ 166.3.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.71 (3H, s), 6.83-7.34 (1H, m),7.68-8.02 (1H, m), 8.02-8.32 (1H, m), 12.68-13.33 (1H, m).

75e) 2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine

To a solution of 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (500 mg)in EtOAc (10 mL) was added mCPBA (1393 mg) at 0° C. After stirring for10 h, the mixture was quenched with water, and extracted with ethylacetate, and the extract was washed with brine, and dried over magnesiumsulfate. The crude material was recrystallized from ethyl acetate togive 2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (593 mg).

MS (API+): [M+H]⁺ 198.2.

¹H NMR (300 MHz, DMSO-d₆) δ 3.52 (3H, s), 7.32-7.41 (1H, m), 7.50-7.61(1H, m), 7.67-7.76 (1H, m), 8.53-8.63 (1H, m).

75f)2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine

Sodium hydride (146 mg) was added to a solution of2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) and[2-(chloromethoxy)ethyl]trimethylsilane (609 mg) in DMF (3 mL) at roomtemperature. The mixture was stirred at room temperature under a dryatmosphere (CaCl₂ tube) for 1 h. The reaction mixture was diluted withMeOH (2 mL), and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, eluted with 0%-30% EtOAc in hexane)to give2-(methylsulfonyl)-1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-imidazo[4,5-b]pyridine(250 mg) as light brown oil.

MS (API+): [M+H]⁺ 328.3.

75g)1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(281 mg),2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine(240 mg) and NaH (35.2 mg) in DMF(dry) (3 mL) was heated at 200° C. for3 h under microwave irradiation. The reaction mixture was diluted withMeOH, and concentrated in vacuo. The residue was diluted with 6N HCl.The mixture was neutralized with aq. NaHCO₃ at 0° C. and extracted withEtOAc. The organic layer was separated, washed with water and brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, eluted with 0%-100% EtOAc in hexane)to give1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(40 mg) as white crystals.

MS (API+): [M+H]⁺ 373.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.1 Hz), 3.99 (2H, q, J=7.1Hz), 7.10-7.26 (2H, m), 7.55-7.64 (2H, m), 7.66-7.72 (1H, m), 7.73-7.84(3H, m), 7.97-8.06 (1H, m), 8.11-8.23 (1H, m).

Example 851-ethyl-3-{4-[(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

85a) N-benzyl-N-methyl-2-nitropyridin-3-amine

The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 ml) and3-chloro-2-nitropyridine (5 g) was stirred at 60° C. under N₂ overnight.The reaction mixture was concentrated in vacuo. The residue was purifiedby column chromatography (silica gel, eluted with 0%-30% EtOAc inhexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as darkyellow oil.

MS (API+): [M+H]⁺ 244.1.

¹H NMR (300 MHz, DMSO-d₆) δ 2.75 (3H, s), 4.44 (2H, s), 7.16-7.47 (5H,m), 7.51-7.62 (1H, m), 7.72-7.82 (1H, m), 7.92-8.02 (1H, m).

85b) N³-methylpyridine-2,3-diamine

A mixture of N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) and 10%Pd—C (0.569 g) in EtOH (50 mL) was hydrogenated under balloon pressureat room temperature over weekend. The catalyst was removed by filtrationand the filtrate was concentrated in vacuo to giveN³-methylpyridine-2,3-diamine (1.14 g) as pale yellow oil.

MS (API+): [M+H]⁺ not detected.

¹H NMR (300 MHz, DMSO-d₆) δ 2.68 (3H, d, J=4.9 Hz), 4.85 (1H, q, J=4.9Hz), 5.35 (2H, s), 6.41-6.58 (2H, m), 7.21-7.32 (1H, m).

85c) 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

CDI (2.251 g) was added to a solution of N³-methylpyridine-2,3-diamine(1.14 g) in THF(dry) (50 mL) at room temperature. The mixture wasstirred at room temperature under a dry atmosphere (CaCl₂ tube) overweekend. The reaction mixture was concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 0%-100% EtOAcin hexane) to give 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.1 g) as a white solid.

MS (API+): [M+H]⁺ not detected.

¹H NMR (300 MHz, DMSO-d₆) δ 3.29 (3H, s), 7.02 (1H, dd, J=7.9, 5.3 Hz),7.40 (1H, dd, J=7.9, 1.5 Hz), 7.90 (1H, dd, J=5.3, 1.5 Hz), 11.51 (1H,brs).

85d) 2-chloro-1-methyl-1H-imidazo[4,5-b]pyridine

The mixture of 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.1g) and phosphorus oxychloride (6.87 mL) was stirred at 100° C. under adry atmosphere (CaCl₂ tube) for 5 h. The mixture was neutralized withsat.NaHCO₃ at 0° C. and extracted with EtOAc. The organic layer wasseparated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-50% EtOAc in hexane) to give2-chloro-1-methyl-1H-imidazo[4,5-b]pyridine (600 mg) as a white solid.

MS (API+): [M+H]⁺ 168.0.

¹H NMR (300 MHz, DMSO-d₆) δ 3.83 (3H, s), 7.34 (1H, dd, J=8.1, 4.9 Hz),8.06 (1H, dd, J=8.1, 1.7 Hz), 8.42 (1H, dd, J=4.9, 1.7 Hz).

85e)1-ethyl-3-{4-[(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of sodium hydride (14.32 mg),2-chloro-1-methyl-1H-imidazo[4,5-b]pyridine (100 mg) and1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(152 mg) in DMF (3 ml) was stirred at 180° C. under a dry atmosphere(CaCl₂ tube) for 20 min. The mixture was neutralized with 1N HCl at 0°C. and extracted with EtOAc. The organic layer was separated, washedwith water and brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by column chromatography (silica gel, eluted with0%-100% EtOAc in hexane) to give1-ethyl-3-{4-[(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(150 mg) as white crystals.

MS (API+): [M+H]⁺ 387.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.2 Hz), 3.80 (3H, s), 3.99(2H, q, J=7.2 Hz), 7.14-7.28 (2H, m), 7.60-7.68 (2H, m), 7.66-7.74 (1H,m), 7.78-7.86 (2H, m), 7.87-7.95 (1H, m), 7.96-8.06 (1H, m), 8.21-8.35(1H, m).

Example 861-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

86a) N-benzyl-N-methyl-3-nitropyridin-2-amine

The mixture of 2-chloro-3-nitropyridine (15 g), Na₂CO₃ (10.03 g) andN-methylbenzylamine (24.42 mL) in THF (150 mL) was stirred at 80° C.under a dry atmosphere (CaCl₂ tube) overnight. The mixture wasneutralized with 1N HCl at 0° C. and extracted with EtOAc. The organiclayer was separated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, eluted with 0%-30% EtOAc in hexane) to giveN-benzyl-N-methyl-3-nitropyridin-2-amine (19 g) as yellow oil.

MS (API+): [M+H]⁺ not detected.

¹H NMR (300 MHz, CDCl₃) δ 2.81 (3H, s), 4.94 (2H, s), 6.59-6.82 (1H, m),7.21-7.44 (5H, m), 8.09-8.18 (1H, m), 8.27-8.43 (1H, m).

86b) N²-methylpyridine-2,3-diamine

A mixture of N-benzyl-N-methyl-3-nitropyridin-2-amine (15 g) and 10%Pd—C (6.56 g) in EtOH (300 mL) was hydrogenated under balloon pressureat room temperature over weekend. The catalyst was removed by filtrationand the filtrate was concentrated in vacuo to giveN²-methylpyridine-2,3-diamine (7.00 g) as a tan solid.

MS (API+): [M+H]⁺ not detected.

¹H NMR (300 MHz, DMSO-d₆) δ 2.81 (3H, d, J=4.9 Hz), 4.60 (2H, s), 5.56(1H, q, J=4.9 Hz), 6.32 (1H, dd, J=7.2, 4.9 Hz), 6.64 (1H, dd, J=7.2,1.7 Hz), 7.37 (1H, dd, J=4.9, 1.7 Hz).

86c) 3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A solution of N²-methylpyridine-2,3-diamine (7 g) and CDI (13.82 g) inTHF (100 mL) was refluxed for 5 h. The reaction mixture was concentratedin vacuo. The residue was purified by column chromatography (NH silicagel, eluted with 0%-100% EtOAc in hexane) to give3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7 g) as a lightbrown solid.

MS (API+): [M+H]⁺ not detected.

¹H NMR (300 MHz, DMSO-d₆) δ 3.30 (3H, s), 6.96-7.01 (1H, m), 7.24-7.34(1H, m), 7.90-7.98 (1H, m).

86d) 2-chloro-3-methyl-3H-imidazo[4,5-b]pyridine

The mixture of 3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.0g) in phosphorus oxychloride (10 g) was stirred at 100° C. under a dryatmosphere (CaCl₂ tube) for 5 h. The mixture was neutralized withsat.NaHCO₃ at 0° C. and extracted with EtOAc. The organic layer wasseparated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-50% EtOAc in hexane) to give2-chloro-3-methyl-3H-imidazo[4,5-b]pyridine (230 mg) as a white solid.

MS (API+): [M+H]⁺ 168.0.

¹H NMR (300 MHz, DMSO-d₆) δ 3.80 (3H, s), 7.33 (1H, dd, J=8.0, 4.9 Hz),8.04 (1H, dd, J=8.0, 1.5 Hz), 8.39 (1H, dd, J=4.9, 1.5 Hz).

86e)1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-3-methyl-3H-imidazo[4,5-b]pyridine (150 mg) was added to asolution of1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(228 mg) and NaH (39.4 mg) in DMF (2 mL) at 100° C. The mixture wasstirred at 180° C. under a dry atmosphere (CaCl₂ tube) for 1 h. Themixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc.The organic layer was separated, washed with water and brine, dried overMgSO₄ and concentrated in vacuo. The residue was purified by columnchromatography (NH silica gel, eluted with 0%-100% EtOAc in hexane) togive1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(200 mg) as white crystals.

MS (API+): [M+H]⁺ 387.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.2 Hz), 3.78 (3H, s), 3.99(2H, q, J=7.2 Hz), 7.14-7.27 (2H, m), 7.58-7.67 (2H, m), 7.67-7.74 (1H,m), 7.76-7.86 (3H, m), 7.97-8.06 (1H, m), 8.16-8.28 (1H, m).

Example 963,3-dimethyl-1-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

96a) 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine

MeI (44.7 mL) was added to a mixture of K₂CO₃ (148 g) and1H-imidazo[4,5-b]pyridine-2-thiol (54 g) in DMF (500 mL) at roomtemperature. The mixture was stirred at room temperature under a dryatmosphere (CaCl₂ tube) overnight. The mixture was poured into water atroom temperature and the mixture was extracted with EtOAc. The organiclayer was separated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo to give3-methyl-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine as a crude product(12 g).

The mixture of 3-methyl-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (12g) and mCPBA (33.0 g) in EtOAc (200 mL) was stirred at room temperatureunder a dry atmosphere (CaCl₂ tube) for 3 h. The mixture was neutralizedwith sat.NaHCO₃ at 0° C. and extracted with EtOAc. The organic layer wasseparated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-30% EtOAc in hexane) to give3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (10 g) as whitecrystals.

MS (API+): [M+H]⁺ 212.1.

¹H NMR (300 MHz, DMSO-d₆) δ 3.66 (3H, s), 4.12 (3H, s), 7.43-7.56 (1H,m), 8.25-8.38 (1H, m), 8.56-8.67 (1H, m).

96b)3,3-dimethyl-1-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was addedto a solution of1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(119 mg) and NaH (20.45 mg) in DMF (2 mL) at 100° C. The mixture washeated at 180° C. for 30 min under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated under reduced pressure.The residue was purified by column chromatography (NH silica gel, elutedwith 0%-50% EtOAc in hexane) to give3,3-dimethyl-1-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(120 mg) as white crystals.

MS (API+): [M+H]⁺ 386.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.46 (6H, s), 3.77 (3H, s), 7.09-7.28 (2H,m), 7.55-7.69 (4H, m), 7.75-7.92 (2H, m), 8.13 (1H, m), 8.17-8.28 (1H,m).

Example 973-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

97a)3-[4-(benzyloxy)phenyl]-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaH (1.260 g) was added to a solution of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g)and 1-iodopropane (3.07 mL) in DMF (50 mL) at room temperature. Themixture was stirred at room temperature under a dry atmosphere (CaCl₂tube) for 1 h. The reaction mixture was diluted with MeOH andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-50% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.5 g) as dark yellow oil.

MS (API+): [M+H]⁺ 360.4.

¹H NMR (300 MHz, DMSO-d₆) δ 0.71-1.12 (3H, m), 1.60-1.88 (2H, m),3.76-4.02 (2H, m), 5.19 (2H, s), 7.08-7.23 (3H, m), 7.28-7.58 (7H, m),7.59-7.69 (1H, m), 7.89-8.00 (1H, m).

97b)3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.5 g) and 10% Pd—C (0.444 g) in EtOH (40 mL) was hydrogenated underballoon pressure at room temperature for 3 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.05 g) as a light brown solid.

MS (API+): [M+H]⁺ 270.1.

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.98 (3H, m), 1.63-1.82 (2H, m).3.77-3.95 (2H, m), 6.82-6.97 (2H, m), 7.07-7.20 (1H, m), 7.29-7.44 (2H,m), 7.57-7.69 (1H, m), 7.87-8.00 (1H, m), 9.21-10.52 (1H, m).

97c)3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (320 mg) was addedto a solution of3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(400 mg) and NaH (65.3 mg) in DMF (5 ml) at 100° C.,. The mixture washeated at 180° C. for 30 min under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg) as white crystals.

MS (API+): [M+H]⁺ 401.2.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-1.00 (3H, m), 1.68-1.86 (2H, m), 3.78(3H, s), 3.86-3.97 (2H, m), 7.13-7.29 (2H, m), 7.59-7.66 (2H, m),7.67-7.73 (1H, m), 7.74-7.86 (3H, m), 7.95-8.06 (1H, m), 8.14-8.29 (1H,m).

Example 981-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

98a)3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaH (1.260 g) was added to a solution of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g)and 2-iodopropane (3.15 mL) in DMF (50 mL) at room temperature. Themixture was stirred at room temperature under a dry atmosphere (CaCl₂tube) for 1 h. The reaction mixture was diluted with MeOH andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-50% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.5 g) as dark yellow oil.

MS (API+): [M+H]⁺ 360.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.50 (6H, d, J=7.2 Hz), 4.64-4.80 (1H, m),5.19 (2H, s), 7.05-7.24 (3H, m), 7.28-7.59 (7H, m), 7.70-7.79 (1H, m),7.87-8.00 (1H, m).

98b)3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.5 g) and 10% Pd—C (0.444 g) in EtOH (40 mL) was hydrogenated underballoon pressure at room temperature for 5 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(670 mg) as a light brown solid.

MS (API+): [M+H]⁺ 270.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.40-1.59 (6H, m), 4.62-4.80 (1H, m),6.81-6.94 (2H, m), 7.04-7.19 (1H, m), 7.29-7.42 (2H, m), 7.63-7.81 (1H,m), 7.87-8.02 (1H, m), 9.52-9.91 (1H, m).

98c)1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (270 mg) was addedto a solution of3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(330 mg) and NaH (53.9 mg) in DMF (5 ml) at 100° C. The mixture washeated at 180° C. for 30 min under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(150 mg) as white crystals.

MS (API+): [M+H]⁺ 401.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.43-1.67 (6H, m), 3.81 (3H, s), 4.64-4.91(1H, m), 7.08-7.31 (2H, m), 7.54-7.70 (2H, m), 7.70-7.89 (4H, m),7.93-8.07 (1H, m), 8.18-8.28 (1H, m).

Example 991-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

99a)3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300mg), cyclopropylboronic acid (731 mg), TEA (1976 μl), pyridine (1835μl), copper(II) acetate (1030 mg) and THF (4727 μl) was heated at 140°C. for 30 min under microwave irradiation. The solid was removed byfiltration, and the filtrate was concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-30%EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(120 mg) as white crystals.

MS (API+): [M+H]⁺ 358.1.

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.01 (2H, m), 1.01-1.11 (2H, m),2.92-3.07 (1H, m), 5.18 (2H, s), 7.08-7.21 (3H, m), 7.30-7.46 (3H, m),7.45-7.53 (4H, m), 7.53-7.62 (1H, m), 7.89-8.00 (1H, m).

99b)1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(120 mg) and 10% Pd—C (17.87 mg) in EtOH (10 mL) was hydrogenated underballoon pressure at room temperature for 2 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(89 mg) as a white solid.

MS (API+): [M+H]⁺ 268.1.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-1.00 (2H, m), 1.01-1.11 (2H, m),2.92-3.07 (1H, m), 6.83-6.95 (2H, m), 7.07-7.20 (1H, m), 7.28-7.40 (2H,m), 7.50-7.62 (1H, m), 7.87-8.00 (1H, m), 9.76 (1H, brs).

99c)1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (79 mg) was addedto a solution of1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) and NaH (17.96 mg) in DMF (2 ml) at 100° C. The mixture was soheated at 180° C. for 1 h under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(80 mg) as white crystals.

MS (API+): [M+H]⁺ 399.2.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94-1.03 (2H, m), 1.03-1.13 (2H, m),2.93-3.10 (1H, m), 3.78 (3H, s), 7.16-7.27 (2H, m), 7.58-7.67 (3H, m),7.70-7.87 (3H, m), 7.94-8.06 (1H, m), 8.15-8.27 (1H, m).

Example 1001-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

100a)3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Difluorochloroacetic acid sodium salt (1.922 g) was added to a solutionof 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2g), lithium bromide (1.095 g) and NaH (0.290 g) in DMF(20 ml) at 0° C.The mixture was stirred at 140° C. under a dry atmosphere (CaCl₂ tube)for 1 h. The reaction mixture was diluted with MeOH and concentrated invacuo. The residue was purified by column chromatography (NH silica gel,eluted with 0%-30% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(420 mg) as a white solid.

MS (API+): [M+H]⁺ 368.1.

¹H NMR (300 MHz, DMSO-d₆) δ 5.20 (2H, s), 6.99-8.28 (13H, m).

100b)1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(420 mg) and 10% Pd—C (60.8 mg) in EtOH (50 mL) was hydrogenated underballoon pressure at room temperature for 3 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg) as a white solid.

MS (API+): [M+H]⁺ 278.1.

¹H NMR (300 MHz, DMSO-d₆) δ 6.85-6.98 (2H, m), 7.16-7.29 (1H, m),7.32-7.45 (2H, m), 7.60-8.04 (2H, m), 8.05-8.16 (1H, m), 9.82 (1H, s).

100c)1-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-1-methyl-1H-benzimidazole (70 mg) was added to a solution of1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(122 mg) and NaH (25.2 mg) in DMF (3 mL) at 100° C. The mixture washeated at 180° C. for 1 h under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give1-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(80 mg) as white crystals.

MS (API+): [M+H]⁺ 408.1.

¹H NMR (300 MHz, DMSO-d₆) δ 3.77 (3H, s), 7.08-7.34 (3H, m), 7.37-7.54(2H, m), 7.57-7.67 (2H, m), 7.66-8.09 (4H, m), 8.12-8.19 (1H, m).

Example 1011-(difluoromethyl)-3-{(4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was addedto a solution of1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(124 mg) and NaH (25.6 mg) in DMF (3 mL) at 100° C. The mixture washeated at 180° C. for 1 h under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give1-(difluoromethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(50 mg) as white crystals.

MS (API+): [M+H]⁺ 409.1.

¹H NMR (300 MHz, DMSO-d₆) δ 3.78 (3H, s), 7.07-7.37 (2H, m), 7.54-8.37(9H, m).

Example 1023,3-dimethyl-1-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

NaH (17.28 mg) was added to a solution of1-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(40 mg) and MeI (10.13 μl) in DMF(1 mL) at room temperature. The mixturewas stirred at room temperature under a dry atmosphere (CaCl₂ tube) for1 h. The reaction mixture was diluted with MeOH and concentrated invacuo. The residue was purified by column chromatography (NH silica gel,eluted with 0%-50% EtOAc in hexane) to give3,3-dimethyl-1-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(35 mg) as white crystals.

MS (API+): [M+H]⁺ 385.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (6H, s), 3.76 (3H, s), 7.09-7.25 (3H,m), 7.37-7.52 (2H, m), 7.53-7.66 (4H, m), 7.80-7.93 (1H, m), 8.06-8.20(1H, m).

Example 1031-cyclopropyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-1-methyl-1H-benzimidazole (15 mg) was added to a solution of1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(24.06 mg) and NaH (5.40 mg) in DMF (1 mL) at 100° C. The mixture washeated at 180° C. for 1 h under microwave irradiation. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give1-cyclopropyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(5.0 mg) as white crystals.

MS (API+): [M+H]⁺ 398.2.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94-1.04 (2H, m), 1.04-1.13 (2H, m),2.96-3.08 (1H, m), 3.77 (3H, s), 7.10-7.29 (3H, m), 7.38-7.51 (2H, m),7.54-7.67 (3H, m), 7.67-7.79 (2H, m), 7.95-8.06 (1H, m).

Example 1066-chloro-1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

106a) tert-butyl (2,5-dichloropyridin-3-yl)carbamate

Boc₂O (17.05 mL) was added to a solution of 2,5-dichloropyridin-3-amine(11.4 g) and NaHMDS (1.9M, 81′ mL) in THF (200 ml) at 0° C. The mixturewas stirred at 0° C. under a dry atmosphere (CaCl₂ tube) for 1 h. Themixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc.The organic layer was separated, washed with water and brine, dried overMgSO₄ and concentrated in vacuo. The residue was purified by columnchromatography (NH silica gel, eluted with 0%-20% EtOAc in hexane) togive tert-butyl (2,5-dichloropyridin-3-yl)carbamate (15.6 g) ascolorless oil.

MS (API+): [M+H]⁺ not detected.

¹H NMR (300 MHz, DMSO-d₆) δ 1.48 (9H, s), 8.20-8.23 (1H, m), 8.23-8.26(1H, m), 9.07-9.11 (1H, m).

106b)3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of tert-butyl (2,5-dichloropyridin-3-yl)carbamate (7.0 g),4-(benzyloxy)aniline (7.95 g),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.231 g), Pd₂(dba)₃(0.974 g) and sodium tert-butoxide (3.58 g) in toluene (160ml)-2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight. Thereaction mixture was concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, eluted with 0%-100% EtOAc in hexane)to give intermediate. To the intermediate in DMF (100 mL) were added NaH(3.19 g) and ethyl iodide (20.75 g). The mixture was stirred at roomtemperature under a dry atmosphere (CaCl₂ tube) for 1 h. The reactionmixture was diluted with MeOH and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 0%-50%EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2 g) as a colorless solid.

MS (API+): [M+H]⁺ 380.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.21-1.36 (3H, m), 3.88-4.02 (2H, m), 5.18(2H, s), 7.10-7.21 (2H, m), 7.29-7.56 (7H, m), 7.85-7.93 (1H, m),7.94-8.00 (1H, m).

106c)6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(500 mg) and 10% Pd—C (140 mg) in EtOAc (10 mL) was hydrogenated underballoon pressure at room temperature for 3 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, eluted with 0%-50%EtOAc in hexane) to give6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(70 mg) as a white solid.

MS (API+): [M+H]⁺ 290.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.32 (3H, m), 3.86-4.01 (2H, m),6.83-6.96 (2H, m), 7.26-7.46 (2H, m), 7.84-7.94 (1H, m), 7.92-8.04 (1H,m), 9.74 (1H, s).

106d)6-chloro-1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-Chloro-1-methyl-1H-benzimidazole (50 mg) was added to a solution of6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(90 mg) and NaH (13.2 mg) in DMF (2 mL) at room temperature. The mixturewas heated at 180° C. for 30 min under microwave irradiation. Thereaction mixture was diluted with MeOH and concentrated in vacuo. Theresidue was purified by column chromatography (NH silica gel, elutedwith 0%-50% EtOAc in hexane) to give6-chloro-1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) as colorless crystals.

MS (API+): [M+H]⁺ 420.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.34 (3H, m), 3.76 (3H, s), 3.92-4.04(2H, m), 7.09-7.29 (2H, m), 7.37-7.52 (2H, m), 7.54-7.65 (2H, m),7.69-7.81 (2H, m), 7.93-7.99 (1H, m), 7.99-8.07 (1H, m).

Anal. Calcd for

C₂₂H₁₈N₅O₂Cl: C, 62.93; H, 4.32; N, 16.68; Cl, 8.44. Found: C, 62.74; H,4.38; N, 16.40; Cl,

Mp: 208-210° C.

Example 1076-chloro-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was addedto a solution of6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(127 mg) and NaH (18.74 mg) in DMF (2 mL) at room temperature. Themixture was heated at 180° C. for 30 min under microwave irradiation.The reaction mixture was diluted with MeOH and concentrated in vacuo.The residue was purified by column chromatography (NH silica gel, elutedwith 0%-50% EtOAc in hexane) to give6-chloro-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(40 mg) as colorless crystals.

MS (API+): [M+H]⁺ 421.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24-1.41 (3H, m), 3.77 (3H, s), 3.93-4.03(2H, m), 7.15-7.28 (1H, m), 7.60-7.68 (2H, m), 7.72-7.86 (3H, m),7.94-7.99 (1H, m), 7.99-8.08 (1H, m), 8.18-8.27 (1H, m).

Example 1081-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

108a)3-[4-(benzyloxy)phenyl]-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

The mixture of3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1 g), zinc cyanide (2.474 g),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.216 g),Pd₂(dba)₃ (0.241 g) and DMF (20 mL) was heated at 150° C. for 1 h undermicrowave irradiation. The solid was removed by filtration, and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(710 mg) as colorless oil.

MS (API+): [M+H]⁺ 371.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.35 (3H, m), 3.85-4.09 (2H, m), 5.19(2H, s), 7.08-7.24 (2H, m), 7.28-7.57 (7H, m), 8.11-8.22 (1H, m),8.38-8.50 (1H, m).

108b)1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(500 mg) and 10% Pd—C (71.8 mg) in EtOAc (50 mL) was hydrogenated underballoon pressure at room temperature for 1 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, eluted with 0%-50%EtOAc in hexane) to give1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(90 mg) as a white solid.

MS (API+): [M+H]⁺ 281.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24-1.34 (3H, m), 3.90-4.01 (2H, m),6.81-6.99 (2H, m), 7.29-7.39 (2H, m), 8.12-8.19 (1H, m), 8.38-8.48 (1H,m), 9.71-9.84 (1H, m).

108c)1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (45 mg) was addedto a solution of1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(61.5 mg) and NaH (9.0 mg) in DMF (1 mL) at room temperature. Themixture was heated at 180° C. for 30 min under microwave irradiation.The reaction mixture was diluted with MeOH and concentrated underreduced pressure. The residue was purified by column chromatography (NHsilica gel, eluted with 0%-50% EtOAc in hexane) to give1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(11 mg) as white crystals.

MS (API+): [M+H]⁺ 412.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.40 (3H, m), 3.78 (3H, s), 3.94-4.08(2H, m), 7.14-7.26 (1H, m), 7.60-7.71 (2H, m), 7.71-7.88 (3H, m),8.18-8.30 (2H, m), 8.44-8.54 (1H, m).

Example 1091-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

2-Chloro-1-methyl-1H-benzimidazole (15 mg) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(25.5 mg) and sodium hydride (4.0 mg) in DMF (1.0 mL) at roomtemperature. The mixture was heated at 180° C. for 30 min undermicrowave irradiation. The reaction mixture was diluted with MeOH andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-30% EtOAc in hexane) to give1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile(5 mg) as white crystals.

MS (API+): [M+H]⁺ 411.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.36 (3H, m), 3.77 (3H, s), 3.92-4.09(2H, m), 7.08-7.33 (2H, m), 7.38-7.53 (2H, m), 7.55-7.67 (2H, m),7.68-7.82 (2H, m), 8.12-8.31 (1H, m), 8.41-8.59 (1H, m).

Example 1121-ethyl-3-{4-[(1-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

112a) 2-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-benzimidazole

To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-2-thiol (500 mg) inacetone (5 mL) were added K₂CO₃ (1344 mg) and MeI (0.223 ml) at roomtemperature. After stirring for 1 h, the mixture was quenched withwater, and extracted with ethyl acetate, and the extract was washed withbrine and dried over magnesium sulfate. The residue was purified bycolumn chromatography (silica gel, eluted with 40%-90% EtOAc in hexane)to give 2-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-benzimidazole (545 mg)as a white solid.

MS (API+): [M+H]⁺ 169.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.69 (4H, br. s.), 2.47-2.65 (4H, m), 3.33(3H, s), 11.43-11.98 (1H, m).

112b) 2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole

To a solution of 2-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-benzimidazole(280 mg) in EtOAc (5 mL) was added mCPBA (766 mg) at 0° C. Afterstirring for 10 h, the mixture was quenched with water, and extractedwith ethyl acetate, and the extract was washed with brine, and driedover magnesium sulfate. The residue was purified by columnchromatography (silica gel, eluted with 20%-80% EtOAc in hexane) to give2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (200 mg) as whitecrystals.

MS (API+): [M+H]⁺ 201.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.67-1.88 (4H, m), 2.51-2.65 (4H, m), 3.23(3H, s), 13.17 (1H, none)

112c) 1-methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole

Sodium hydride (55.8 mg) (60% in mineral oil) was added to a solution of2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (233 mg) and MeI(0.080 mL) in DMF(dry) (10 ml) at room temperature. The mixture wasstirred at room temperature under a dry atmosphere (CaCl₂ tube) for 1 h.The reaction mixture was diluted with MeOH (2 mL), and concentrated invacuo. The residue was purified by column chromatography (silica gel,eluted with 0%-30% EtOAc in hexane) to give1-methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (200 mg)as a white solid.

MS (API+): [M+H]⁺ 215.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.59-1.93 (3H, m), 2.50 (5H, br. s.),3.18-3.43 (6H, m)

112d)1-ethyl-3-{4-[(1-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

1-Methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (84 mg)was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) and NaH (18.8 mg) (60% in mineral oil) in DMA (3 ml) in amicrowave vessel. The vessel was sealed and subjected to microwaveirradiation (at 120° C. set by IR sensor, fixed hold time: on,Absorption level: High) for 1 h in a Biotage Initiator 60EXP. Themixture was poured into water, and the mixture was extracted with ethylacetate. The extract was washed with brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, eluted with 20%-100%EtOAc in hexane) to give1-ethyl-3-{4-[(1-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(8.90 mg) as white crystals.

MS (API+): [M+H]⁺ 390.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (4H, s), 1.64-1.83 (5H, m), 2.31-2.40(3H, m), 2.42-2.47 (2H, m), 3.35-3.40 (1H, m), 3.90-4.03 (2H, m),7.11-7.22 (1H, m), 7.28-7.39 (1H, m), 7.59-7.72 (3H, m), 7.93-8.02 (1H,m).

Example 1151-ethyl-3-[4-(3H-imidazo[4,5-c]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

115a) 1H-imidazo[4,5-c]pyridine-2-thiol

To a solution of pyridine-3,4-diamine (5 g) in EtOH (80 mL) was addedcarbon disulfide (10 mL) at room temperature. The mixture was stirred at40° C. under a dry atmosphere (CaCl₂ tube) for 10 h. The mixture wascooled to room temperature. The resulting white solid was collected byfiltration and washed with ether to give1H-imidazo[4,5-c]pyridine-2-thiol (6.1 g) as a white solid.

MS (API+): [M+H]⁺ 152.0

¹H NMR (300 MHz, DMSO-d₆) δ 7.17 (1H, d, J=5.29 Hz), 8.25 (1H, d, J=5.67Hz), 8.38 (1H, s), 12.87 (2H, bra s.).

115b) 2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine

To a solution of 1H-imidazo[4,5-c]pyridine-2-thiol (4 g) in acetone (50mL) were added potassium carbonate (11 g) and MeI (1.8 ml). Afterstirring for 3 h, the mixture was filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, eluted with 10%-70% EtOAc in hexane) to give2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine (4.07 g) as a yellow solid.

MS (API+): [M+H]⁺ 166.0.

¹H NMR (300 MHz, DMSO-d₆) δ 2.72 (3H, s), 7.42-7.52 (1H, m 8.09-8.27(1H, m), 8.77 (1H, s)

115c) 2-(methylsulfonyl)-1H-imidazo[4,5-c]pyridine

To a solution of 2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine (4 g) inEtOAc (50 mL) was added mCPBA (11.14 g) at 0° C. After stirring for 10h, the mixture was quenched with water, and extracted with ethylacetate, and the extract was washed with brine, and dried over magnesiumsulfate. The crude material was recrystallized from ethyl acetate togive 2-(methylsulfonyl)-1H-imidazo[4,5-c]pyridine (1.100 g) as a whitesolid.

MS (API+): [M+H]⁺ 198.1.

¹H NMR (300 MHz, DMSO-d₆) δ 3.39 (3H, s), 7.76-8.03 (1H, m), 8.21-8.31(1H, m), 9.23 (1H, s), 13.93-14.52 (1H, m).

115d)2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-c]pyridine

NaH (122 mg) (60% in mineral oil) was added to a solution of2-(methylsulfonyl)-1H-imidazo[4,5-c]pyridine (500 mg) and2-(trimethylsilyl)ethoxymethyl chloride (0.538 mL) in DMF (3 mL) at roomtemperature. The mixture was stirred at room temperature under a dryatmosphere (CaCl₂ tube) for 1 h. The reaction mixture was diluted withMeOH (2 ml), and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, eluted with 0%-30% EtOAc in hexane)to give2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-c]pyridine(330 mg) as a light brown solid.

MS (API+): [M+H]⁺ 328.1.

115e)1-ethyl-3-[4-(3H-imidazo[4,5-c]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2-(Methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-c]pyridine(350 mg) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(220 mg) and NaH (41.4 mg) (60% in mineral oil) in THF (1 mL) in amicrowave vessel. The vessel was sealed and subjected to microwaveirradiation (at 120° C. set by IR sensor, fixed hold time: on,Absorption level: High) for 30 min in a Biotage Initiator 60EXP. Themixture was poured into water, and extracted with ethyl acetate, and theextract was washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, eluted with 0%-20% MeOH in EtOAc) to giveintermediate (230 mg) as a white solid. To a solution of theintermediate (120 mg) in THF (2 mL) was added TBAF (0.955 mL) in amicrowave vessel. The vessel was sealed and subjected to microwaveirradiation (at 100° C. set by IR sensor, fixed hold time: on,Absorption level: Normal) for 1 h in a Biotage Initiator 60EXP. Themixture was poured into water, the mixture was extracted with ethylacetate, and the extract was washed with brine (20 mL×2), dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by column chromatography (NH-silica gel, eluted with 0%-5%Methanol in EtOAc; and then, silica gel, eluted with 0%-5% Methanol inEtOAc) to give1-ethyl-3-[4-(3H-imidazo[4,5-c]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(32.8 mg) as white crystals.

MS (API+): [M+H]⁺ 373.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, none), 3.91-4.10 (2H, m),7.13-7.26 (1H, m), 7.43-7.56 (3H, m), 7.62-7.77 (3H, m), 7.95-8.03 (1H,m), 8.03-8.14 (1H, m), 8.54-8.67 (1H, m).

Example 1181-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

118a) N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine

To a mixture of 4-(benzyloxy)aniline hydrochloride (4.10 g) and2-chloro-5-methyl-3-nitropyridine (3.0 g) in DMF (30 mL) was added TEA(7.27 mL) at room temperature, and the mixture was stirred at roomtemperature for 2 h. The mixture was heated to 60° C. After stirring at60° C. overnight, K₂CO₃ (4.81 g) was added to the mixture. The mixturewas heated to 100° C. and stirred at 100° C. overnight. The mixture waspoured into water and the mixture was extracted with AcOEt. The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(dry charge, silica gel, eluted with 5%-30% AcOEt in hexane) to giveN-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) as ared solid.

¹H NMR (300 MHz, DMSO-d₆) δ 2.26 (3H, s), 5.11 (2H, s), 6.96-7.05 (2H,m), 7.29-7.54 (7H, m), 8.32-8.38 (2H, m), 9.78 (1H, s).

118b) N²-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine

To a solution of N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine(1.33 g) in acetic acid (10 mL) and THF (10 mL) was added zinc (2.59 g)at 0° C., and the mixture was stirred at 0° C. for 2 h. After stirringat room temperature overnight, the mixture was filtered and the filtratewas concentrated in vacuo. The residue was diluted with AcOEt, washedwith sat. NaHCO₃, dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography (NH silica gel, elutedwith 5%-50% AcOEt in hexane) to giveN²-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) as a bluesolid.

MS (API+): [M+H]⁺ 306.4.

¹H NMR (300 MHz, DMSO-d₆) δ 2.08 (3H, s), 4.93 (2H, s), 5.04 (2H, s),6.70 (1H, d, J=1.9 Hz), 6.89 (2H, d, J=9.1 Hz), 7.23-7.54 (9H, m).

118c)3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A solution of N²-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine(0.63 g) and CDI (0.67 g) in THF (20 mL) was refluxed overnight. Themixture was concentrated in vacuo. The residual solid was washed withAcOEt to give3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.64 g) as an off-white solid.

MS (API+): [M+H]⁺ 332.2.

¹H NMR (300 MHz, DMSO-d₆) δ 2.30(3H, s), 5.18 (2H, s), 7.09-7.78 (11H,m), 11.23 (1H, brs).

118d)3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.64 g), iodoethane (0.20 mL) and cesium carbonate (1.26 g) in DMF (5ml) was stirred at 50° C. for 4 h. After stirring at room temperatureover weekend, the mixture was poured into water, and the mixture wasextracted with AcOEt. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo to give3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.68 g) as a brown oil.

MS (API+): [M+H]⁺ 360.2.

118e)1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.68 g) and 10% palladium on carbon (0.30 g) in MeOH (15 mL) washydrogenated under balloon pressure at room temperature for 2 h. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to give1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(0.50 g) as a pale yellow solid.

MS (API+): [M+H]⁺ 270.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (3H, t, J=7.2 Hz), 2.33 (3H, s), 3.92(2H, q, J=7.2 Hz), 6.83-6.91 (2H, m), 7.31-7.39 (2H, m), 7.48 (1H, d,J=1.5 Hz), 7.74-7.81 (1H, m).

118f)1-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(156 mg) and1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(166 mg) in DMF (3 mL) was added NaH (30 mg) at room temperature, andthe mixture was stirred at 150° C. under microwave irradiation for 2 h.The mixture was partitioned between water and AcOEt. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (dry charge, NHsilica gel, eluted with 50%-100% AcOEt in hexane) and columnchromatography (dry charge, silica gel, eluted with 50%-100% AcOEt inhexane), and recrystallized from MeOH to give1-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(43 mg) as white crystals.

MS (API+): [M+H]⁺ 401.3.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2 Hz), 2.37 (3H, s), 3.77(3H, s), 3.96 (2H, q, J=7.2 Hz), 7.20 (1H, dd, J=7.7, 5.1 Hz), 7.54-7.66(3H, m), 7.75-7.87 (4H, m), 8.21 (1H, dd, J=4.9, 1.5 Hz).

mp 217-219° C.

Anal. Calcd for C₂₂H₂₀N₆O₂: C, 65.99; H, 5.03; N, 20.99. Found: C,65.93; H, 5.16; N, 20.89.

Example 1191-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

119a)3-[4-(benzyloxy)phenyl]-1-ethyl-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(190 mg), Pd₂ dba₃ (23 mg),2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl(48 mg) and KOH (145 mg) in dioxane (3 ml) and water (3 mL) was stirredat 100° C. under Ar atmosphere for 6 h. The mixture was cooled to roomtemperature, and cetyltrimethylammonium bromide (50 mg) and iodomethane(0.034 mL) were added. After stirring at 100° C. for 2 h, the mixturewas cooled to room temperature. Iodomethane (0.034 mL) was added to themixture. After stirring at room temperature, the mixture was poured intowater, and the mixture was extracted with AcOEt. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 5%-40% AcOEtin hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(125 mg) as a dark yellow oil.

MS (API+): [M+H]⁺ 376.3.

¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7.2 Hz), 3.88 (3H, s), 3.98(2H, q, J=7.4 Hz), 5.11 (2H, s), 6.90 (1H, d, J=2.3 Hz), 7.06-7.15 (2H,m), 7.29-7.49 (5H, m), 7.53-7.62 (2H, m), 7.73 (1H, d, J=2.6 Hz).

119b)1-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(120 mg) and 10% palladium on carbon (40 mg) in MeOH (10 mL) washydrogenated under balloon pressure at room temperature for 2 h. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to give1-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(75 mg) as white crystals.

MS (API+): [M+H]⁺ 286.1.

¹H NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7.2 Hz), 3.89 (3H, s), 4.00(2H, q, J=7.2 Hz), 6.76 (2H, d, J=8.7 Hz), 6.94 (1H, d, J=2.3 Hz), 7.16(1H, brs), 7.29 (2H, d, J=8.7 Hz), 7.73 (1H, d, J=2.3 Hz).

119c)1-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(67 mg) and1-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(75 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and themixture was stirred at 150° C. under microwave irradiation for 2 h. Themixture was partitioned between water and AcOEt. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (dry charge, NHsilica gel, eluted with 50%-100% AcOEt in hexane) and columnchromatography (dry charge, silica gel, eluted with 50%-100% AcOEt inhexane), and recrystallized from MeOH to give1-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(17 mg) as white crystals.

MS (API+): [M+H]⁺ 417.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2 Hz), 3.77 (3H, s), 3.86(3H, s), 3.98 (2H, q, J=7.2 Hz), 7.20 (1H, dd, J=7.9, 4.9 Hz), 7.50 (1H,d, J=2.3 Hz), 7.58-7.65 (2H, m), 7.73 (1H, d, J=2.3 Hz), 7.76-7.84 (3H,m), 8.21 (1H, dd, J=4.9, 1.3 Hz).

Anal. Calcd for C₂₂H₂₀N₆O₃: C, 63.45; H, 4.84; N, 20.18. Found: C,63.52; H, 4.86; N, 20.12.

Mp: 197-198° C.

Example 1201-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Method A 120a)3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (2.00g), 4-(benzyloxy)aniline hydrochloride (2.91 g),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (381 mg), sodiumt-butoxide (1.90 g) and Pd₂(dba)₃ (302 mg) in 2-propanol (6 mL) andtoluene (24 mL) was stirred at 100° C. under N₂ atmosphere for 24 h. Thereaction mixture was concentrated in vacuo. The residue was dissolved inMeOH, and the precipitate was removed by filtration. The filtrate wasconcentrated and the residue was purified by column chromatography (NHsilica gel, eluted with 15%-50% AcOEt in hexane) to give3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(988 mg) as a colorless solid.

MS (API+): [M+H]⁺ 332.3.

¹H NMR (300 MHz, CDCl₃) δ 2.39 (3H, s), 5.12 (2H, s), 6.87 (1H, d, J=5.3Hz), 7.12 (2H, d, J=9.0 Hz), 7.28-7.50 (5H, m), 7.57 (2H, d, J=8.7 Hz),7.96 (1H, d, J=5.3 Hz), 9.93 (1H, brs).

120b)3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Iodoethane (0.289 mL) was added to a mixture of3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(998 mg) and cesium carbonate (1.96 g) in DMF (10 mL) at roomtemperature. The mixture was stirred at 50° C. for 4 h. The mixture wasdiluted with water at room temperature and extracted with AcOEt. Theorganic layer was separated, washed with water and brine, dried overMgSO₄ and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, eluted with 15%-30% AcOEt in hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(801 mg) as an off-white solid.

MS (API+): [M+H]⁺ 360.4

¹H NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7.2 Hz), 2.61 (3H, s), 4.19(2H, q, J=7.2 Hz), 5.11 (2H, s), 6.81 (1H, d, J=5.3 Hz), 7.10 (2H, d,J=8.7 Hz), 7.30-7.47 (5H, m), 7.53 (2H, d, J=9.1 Hz), 7.91 (1H, d, J=5.3Hz).

120c)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(800 mg) and 10% Pd—C (118 mg) in EtOH (20 mL) was hydrogenated underballoon pressure at room temperature overnight. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneas a colorless solid. To a mixture of this solid and3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (480 mg) in DMF(10 ml) was added 60% sodium hydride (58.9 mg) at 100° C. The mixturewas heated at 180° C. for 30 min under microwave irradiation. Thereaction mixture was diluted with MeOH and concentrated under reducedpressure. The residue was purified by column chromatography (NH silicagel, eluted with 30%-50% AcOEt in hexane and silica gel, eluted with15%-30% AcOEt in hexane). The crude materials were purified by HPLC(C18, eluted with H₂O/MeCN containing 0.1% trifluoroacetic acid). Tothis obtained solution was added sat. NaHCO₃ aq, the mixture wasextracted with AcOEt, and the extract was dried over MgSO₄ andconcentrated in vacuo to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(119 mg) as colorless crystals (Form A).

MS (API+): [M+H]⁺ 401.3

Alternative methods for1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(method B-F) are described below.

Method B 120d)1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(21.4 g) and 10% Pd—C (3.17 g) in EtOH (400 mL) was hydrogenated underballoon pressure at room temperature for 2 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo. The solid waswashed with THF-hexane to give1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(10.90 g) as a solid.

MS (API+): [M+H]⁺ 270.4

¹H NMR (300 MHz, CDCl₃) δ 1.44 (3H, d, J=6.9 Hz), 2.65 (3H, s), 4.21(2H, q, J=6.9 Hz), 6.74 (2H, d, J=8.7 Hz), 6.90 (1H, d, J=5.3 Hz), 7.22(2H, d, J=8.7 Hz), 7.94 (1H, d, J=5.3 Hz).

120e)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(1.0 g) and1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.3 g) in DMF (10 mL) was added 60% NaH (0.23 g) at room temperature,and the mixture was stirred at 180° C. under microwave irradiation for30 min. To the mixture was added EtOH (10 mL). The formed crystals werecollected by filtration and washed with EtOH. This microwave reactionwas repeated two additional times with the same amount of startingmaterial. The combined crystals were recrystallized from EtOH containing5% distilled water (270 mL) and dried under reduced pressure to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(3.3 g) as white crystals (Form A).

MS (API+): [M+H]⁺ 401.3

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.2 Hz), 2.61 (3H, s), 3.77(3H, s), 4.12 (2H, q, J=7.2 Hz), 7.00 (1H, d, J=5.7 Hz), 7.20 (1H, dd,J=7.9, 4.9 Hz), 7.58-7.66 (2H, m), 7.71-7.78 (2H, m), 7.80 (1H, dd,J=7.9, 1.1 Hz), 7.87 (1H, d, J=4.9 Hz), 8.22 (1H, dd, J=4.9, 1.5 Hz).

Anal. Calcd for C₂₂H₂₀N₆O₂: C, 65.99; H, 5.03; N, 20.99. Found: C,65.76; H, 5.07; N, 20.85.

120 g) N²-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine

To a solution of N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine(154.5 g) in THF (1300 mL), acetic acid (260 mL) and water (13 mL) wasslowly added zinc powder (300 g) over 35 min. After zinc was added, themixture was stirred at room temperature for 1 h. The reaction mixturewas filtered through celite, and insoluble materials were washed withTHF (3 L). The filtrate was combined and concentrated. To the residuewere added EtOAc (1.2 L) and 2.5 N NaOH (1.2 L) under ice cooling, andthen the mixture was stirred at room temperature for 30 min. The mixturewas filtered through celite, and insoluble materials were washed withEtOAc (3 L). The organic layer was separated, washed with water (300 mL)and brine (300 mL×2), dried over MgSO₄ and concentrated to give a crudeN²-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (137 g) as blackoil. This product was subjected to the next reaction without furtherpurification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.09 (s, 3H) 4.73 (s, 2H) 5.04 (s, 2H)6.48 (d, J=5.09 Hz, 1H) 6.90 (d, J=9.04 Hz, 2H) 7.26-7.59 (m, 9H).

120 h)3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of N²-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine(91.0 g) in THF (850 mL) was added N,N′-carbonylimidazol (90.8 g) atroom temperature. The mixture was stirred at room temperature for 17 h.To the mixture was added 1 N NaOH (300 mL) over 10 min in ice bath, andthe mixture was stirred for 15 min. To the mixture was added 1 N HCl(460 mL) under ice cooling, and then the mixture was stirred for 15 min.To the mixture was added water (90 mL) at room temperature, and then themixture was stirred for 20 min. The precipitate was collected byfiltration, washed with water (1.3 L), and dried in air blowing for 30min. The precipitate was washed with IPE (1.5 L) and dried in vacuo at55° C. for 2.5 h. The precipitate was suspended in IPE (500 mL), and themixture was stirred at room temperature for 1 h. The precipitate wascollected by filtration, washed with IPE (500 mL), and dried in vacuo togive3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(86 g) as a purple solid.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.34 (s, 3H) 5.18 (s, 2H) 6.92 (d,J=5.65 Hz, 1H) 7.09-7.20 (m, 2H) 7.31-7.55 (m, 7H) 7.80 (d, J=5.27 Hz,1H) 11.44 (s, 1H).

120i)3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(86.1 g) in DMF (860 mL) was added potassium tert-butoxide (87.5 g) withcooling in water bath. To the mixture was added ethyl iodide (122 g),and the mixture was stirred at room temperature for 6 h. The mixture waspoured into EtOAc (1.2 L) and 5% aq. NaCl (1 L). The organic layer wasseparated. The aqueous layer was extracted with EtOAc (500 mL). Thecombined organic phase was washed with brine, dried over MgSO₄, passedthrough a silica gel pad, and evaporated to give3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(88 g) as a black solid. This product was subjected to the next reactionwithout further purification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (t, J=7.06 Hz, 3H) 2.58 (s, 3H)4.08 (q, J=7.03 Hz, 2H) 5.18 (s, 2H) 6.95 (d, J=5.65 Hz, 1H) 7.06-7.22(m, 2H) 7.28-7.58 (m, 8H) 7.82 (d, J=5.27 Hz, 1H).

120j)1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(88.3 g) in DMF (540 mL) and EtOAc (1080 mL) was added 10% Pd—C (9.0 g)at room temperature under Ar atmosphere. The mixture was hydrogenatedunder balloon pressure at room temperature for 5 h. The reaction mixturewas filtered through celite, and then insoluble materials were washedwith EtOAc (500 mL). The filtrate was concentrated in vacuo. The residuewas suspended in EtOAc (350 mL), and the mixture was stirred at roomtemperature for 2 h. The precipitate was collected by filtration, washedwith EtOAc (250 mL) and IPE (100 mL), and dried in vacuo to give1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(56.0 g) as light purple powder.

¹H NMR (300 MHz, DMSO-d₆) S ppm 1.28 (t, J=7.06 Hz, 3H) 2.58 (s, 3H)4.07 (q, J=7.03 Hz, 2H) 6.78-7.00 (m, 3H) 7.22-7.40 (m, 2H) 7.81 (d,J=5.27 Hz, 1H) 9.70 (s, 1H).

Powder X-ray Diffraction (PXRD) Analysis:

Form A is characterized by PXRD Pattern using CuKα X-ray radiation,having peaks selected from a list consisting of:

9.302 angstrom; middle

8.1102 angstrom; middle

5.6255 angstrom; high

5.487 angstrom; middle

4.8439 angstrom; high

4.371 angstrom; high

3.7479 angstrom; low

3.6043 angstrom; high

3.5092 angstrom; middle

3.2178 angstrom; high

d-value.

Method D 120l)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

Crystals of1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg, Form A) was dissolved in EtOH (20 mL) at 80° C. and thesolution was allowed to cool to room temperature. The mixture wasstirred at room temperature for 350 h. The solid was collected byfiltration to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(50 mg) as crystals (Form G).

Crystals of1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(40.0 g, Form A) was dissolved in DMSO (400 mL) at 95° C. and thesolution was allowed to cool to 85° C. To the solution was slowly addedEtOH (400 mL) at 85° C., and then the mixture was allowed to cool to 80°C. To the solution was added seed crystals (Form G: 50 mg) at 80° C. Themixture was stirred and maintained at 73° C. for 20 h. The solid wascollected by filtration and washed with EtOH (500 mL) to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(19.5 g) as white crystals (Form G).

Method E 120m)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

Crystals of1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(600 mg, Form A) was stirred in EtOH (60 mL) at room temperature for 168h. The solid was collected by filtration to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(350 mg) as crystals (Form G).

MS (API+): [M+H]⁺ 401.1.

¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.38 (3H, m), 2.61 (3H, s), 3.78 (3H,s), 4.04-4.18 (2H, m), 6.96-7.04 (1H, m), 7.17-7.25 (1H, m), 7.59-7.66(2H, m), 7.71-7.77 (2H, m), 7.78-7.83 (1H, m), 7.85-7.91 (1H, m),8.16-8.28 (1H, m).

Anal. Calcd for C₂₂H₂₀N₆O₂: C, 65.99; H, 5.03; N, 20.99. Found: C,65.73; H, 5.12; N, 20.85.

Method F 120n)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

Crystals of1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(3.0 g) obtained in 120s′) was dissolved in DMSO (33 mL) at 90° C. Tothe solution was slowly added EtOH (30 mL) at 80-90° C. To the solutionwas added crystals (Form G) obtained in 120m) as seed crystals at 80-90°C. The mixture was stirred at 60-65° C. for 6 h and at room temperaturefor 18 h. The solid was collected by filtration and washed with EtOH (15mL) to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.3 g) as white crystals (Form G).

Method G 120p)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

Crystals of1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(3.0 g) obtained by 120s′) was dissolved in DMSO (33 mL) at 90-95° C. Tothe solution was slowly added AcOEt (30 mL) at 70-90° C. To the solutionwas added crystals (Form G) obtained in 120n) as seed crystals at 80-90°C. The mixture was stirred at 45-50° C. for 25 min and at 70-75° C. for3 h. The mixture was gradually cooled to 0-5° C. and stirred for 1 h.The solid was collected by filtration and washed with AcOEt (15 mL) togive1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.6 g) as white crystals (Form G).

Method H 120q)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(20.4 g, 96.55 mmol) in DMA (117 mL) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(26.0 g, 96.55 mmol) and potassium tert-butoxide (11.4 g) in DMA (96 mL)at room temperature. The mixture was stirred at 95-100° C. for 1.5 h.Water (221 mL) was added at 80-100° C. The precipitate was collected atroom temperature and dried over under reduced pressure to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(35.8 g) as crude product. The obtained crude1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(10.0 g) was dissolved in DMSO (150 mL) at 90-100° C. The solution wasfiltered through filter paper and washed with DMSO (10 mL). The combinedfiltrate was slowly added to a mixture of crystals (Form G: 100 mg)obtained in 120p) (as seed crystals) in AcOEt (100 mL) at 5-30° C. Afterstirring at room temperature for 17 h, the mixture was stirred at 70° C.for 1 h. The mixture was gradually cooled to 25° C. and stirred for 2 h.The mixture was stirred at 0-10° C. for 1 h and at room temperature for1 h. The solids were collected by filtration and dried at 50° C. underreduced pressure to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(8.0 g) as white crystals (Form G).

Method I 120r)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(40.8 g, 193.09 mmol) in DMA (234 mL) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(52.0 g, 193.09 mmol) and potassium tert-butoxide (22.8 g) in DMA (192mL) at room temperature. The mixture was stirred at 90-100° C. for 1 h.Water (442 mL) was added at 80-100° C. The precipitate was collected atroom temperature and dried over under reduced pressure to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(72.4 g) as crude product. The crude1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(60.0 g) was dissolved in DMSO (900 ml) at 90-100° C. The solution wasfiltered through filter paper and washed with DMSO (60 mL). The combinedfiltrate was slowly added to a mixture of crystals (Form G: 600 mg)obtained in 120q) (as seed crystals) in AcOEt (600 mL) at 0-30° C. Themixture was stirred at 70° C. for 0.5 h and cooled to room temperature.After stirring at room temperature for 1 h, the mixture was stirred at0-10° C. for 1 h and at room temperature for 1 h. The solids werecollected by filtration and dried at 50° C. under reduced pressure togive1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(47.9 g) as white crystals (Form G).

MS (ESI+): [M+H]⁺ 401.2

¹H NMR (500 MHz, CDCl₃) δ 1.42 (3H, t), 2.62 (3H, s), 3.84 (3H, s)4.15-4.27 (2H, m), 6.81-6.92 (1H, m), 7.10-7.18 (1H, m), 7.52-7.61 (2H,m), 7.73-7.80 (1H, m), 7.82-7.87 (2H, m), 7.91-7.95 (1H, m), 8.20-8.29(1H, m).

Method J 120s)1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(crystals of Form G)

120s′)A solution of3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (78.4 g, 371.33mmol) in DMA (420 mL) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100.0 g, 371.33 mmol) and potassium tert-butoxide (51.5 g) in DMA (370mL) at room temperature. The mixture was stirred at 90-100° C. for 1 h.Water (780 mL) was added at 90-100° C. The precipitate was collected atroom temperature and dried under reduced pressure to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(127.7 g) as crystals. The obtained crystals (125.0 g) were dissolved inDMSO (1375 mL) at 90-95° C. To the solution was slowly added EtOH (1250mL) at 80-95° C., and then the mixture was allowed to cool to roomtemperature. The solid was collected by filtration and washed with EtOH(625 mL) to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(103.9 g) as crystals.

120s″) The mixture of the obtained crystals (55.0 g) in a solution ofDMSO (275 mL) and EtOH (275 mL) was stirred at 70-75° C. for 0.5 h andthen the mixture was allowed to cool to room temperature. The solid wascollected by filtration and washed with EtOH (165 mL) to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(52.2 g) as crystals (Form A). The obtained crystals (5.0 g) weredissolved in DMSO (50 mL) at 95° C. The solution was filtered throughfilter paper and washed with DMSO (5 mL). To the combined filtrate wasadded EtOH (50 mL) slowly at 73-95° C. To the solution was addedcrystals (Form G: 5 mg) obtained in 120p) (as seed crystals) at 73° C.The mixture was allowed to cool to room temperature. After stirring at70-75° C. for 7 h, the mixture was cooled to room temperature. Afterstirring at 70-75° C. for 8 h, the mixture was cooled to roomtemperature. After stirring at 70-75° C. for 2 h, the mixture wasstirred at room temperature for 1 h, and at 0-10° C. for 1 h. The solidswere collected by filtration and dried at 50° C. under reduced pressureto give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(4.5 g) as white crystals (Form G).

Powder X-ray Diffraction (PXRD) Analysis:

Form G is characterized by PXRD Pattern using CuKα X-ray radiation,having peaks selected from a list consisting of:

9.2245 angstrom; middle

7.8796 angstrom; high

6.763 angstrom; middle

6.2059 angstrom; middle

6.1289 angstrom; middle

5.7268 angstrom; high

5.1275 angstrom; middle

4.638 angstrom; middle

4.267 angstrom; middle

3.9939 angstrom; middle

3.9345 angstrom; middle

3.7921 angstrom; high

3.7479 angstrom; high

3.0579 angstrom; middle

d-value.

Example 1217-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

121a)3-[4-(benzyloxy)phenyl]-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A suspension of3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(360 mg), 2-iodopropane (0.217 mL) and potassium carbonate (180 mg) inDMF (10 ml) was stirred overnight at room temperature. The reactionmixture was poured into water, and the mixture was extracted with AcOEt.The extract was washed with water and brine, dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, eluted with 15%-20% AcOEt in hexane) to givethe title compound (218 mg) as colorless oil.

MS (API+): [M+H]⁺ 374.3

¹H NMR (300 MHz, CDCl₃) δ 1.68 (6H, d, J=6.8 Hz), 2.60 (3H, s),4.72-4.88 (1H, m), 5.11 (2H, s), 6.78 (1H, d, J=5.3 Hz). 7.06-7.13 (2H,m), 7.28-7.47 (5H, m), 7.47-7.55 (2H, m), 7.88 (1H, d, J=5.3 Hz).

121b)7-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(215 mg) and 10% Pd—C (30.6 mg) in EtOH (10 mL) was hydrogenated underballoon pressure at room temperature for 1 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give3-(4-hydroxyphenyl)-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneas a colorless solid. To a solution of this solid in DMF (10 ml) wereadded sodium hydride (27.8 mg) and3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (164 mg) at 100°C. The mixture was heated at 180° C. for 30 min under microwaveirradiation. The precipitate was collected by filtration and washed withAcOEt and MeOH to give the title compound (175 mg) as colorlesscrystals.

MS (API+): [M+H]⁺ 415.4

¹H NMR (300 MHz, DMSO-d₆) δ 1.60 (6H, d, J=6.8 Hz), 2.62 (3H, s), 3.78(3H, s), 4.83 (1H, quin, J=6.8 Hz), 6.98 (1H, d, J=5.3 Hz), 7.20 (1H,dd, J=7.9, 4.9 Hz), 7.57-7.64 (2H, m), 7.68-7.75 (2H, m), 7.80 (1H, dd,J=7.9, 1.5 Hz), 7.84 (1H, d, J=5.3 Hz), 8.22 (1H, dd, J=4.9, 1.5 Hz).

mp 270-271° C.

Example 1226-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

122a)3-[4-(benzyloxy)phenyl]-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaH (84 mg) was added to a solution of3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(346 mg) and 2-iodopropane (0.208 mL) in DMF(dry) (4 mL) at roomtemperature. The mixture was stirred at room temperature under a dryatmosphere (CaCl₂ tube) for 1 h. The mixture was poured into water, andthe mixture was extracted with EtOAc. The organic layer was separated,washed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by column chromatography (NH silica gel,EtOAc/hexane) to give the title compound (283 mg) as a yellow oil.

MS (API+): [M+H]+ 374.2.

122b)3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(283 mg) and 10% palladium on carbon (50% wet) (87 mg) in MeOH (4.2 mL)and EtOAc (4.2 mL) was hydrogenated under balloon pressure at roomtemperature overnight. The solid was filtrated and washed with MeOH (10mL) to remove the catalyst. The filtrate was concentrated in vacuo togive the title compound (210 mg) as a gray solid.

¹H NMR (300 MHz, CDCl₃) δ 1.59 (5H, d, J=7.2 Hz), 2.40 (3H, s), 4.82(1H, t, J=7.0 Hz), 6.60-6.90 (2H, m), 7.25 (2H, s), 7.27-7.32 (2H, m),7.87 (1H, s).

122c)6-methyl-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(198 mg) and3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(177 mg) in DMF (1.5 ml) was added NaH (40.0 mg), and the mixture wasstirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 minunder microwave irradiation. The mixture was poured into water, and themixture was extracted with EtOAc. The organic layer was separated,washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography (silica gel, EtOAc/hexane)to give the title compound (125 mg) as white crystals.

MS (API+): [M+H]+ 415.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.52 (6H, d, J=7.2 Hz), 2.36 (3H, s), 3.77(3H, s), 4.71 (1H, quin, J=6.9 Hz), 7.20 (1H, dd, J=7.9, 4.9 Hz),7.53-7.71 (3H, m), 7.71-7.86 (4H, m), 8.22 (1H, dd, J=4.9, 1.5 Hz).

Anal. Calcd for C₂₃H₂₂N₆O₂: C, 66.65; H, 5.35; N, 20.28. Found: C,66.55; H, 5.44; N, 20.23.

mp 252° C.

Example 1231-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

123a)1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (2.00 g) was added toa solution of p-bromophenol (1.617 g) and NaH (0.427 g) in DMF(dry) (10ml) at 100° C. The mixture was stirred at 100° C. under a dry atmosphereovernight. The reaction mixture was diluted with MeOH, and concentratedin vacuo. The residue was purified by column chromatography (silica gel,eluted with 0%-30% EtOAc in hexane) to give ethyl2-(4-bromophenoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.5 g) as acolorless solid and 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (530 mg) asa colorless solid. The mixture of2-(4-bromophenoxy)imidazo[1,2-a]pyridine (410 mg),1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (164 mg),trans-N,N′-dimethylcyclohexane-1,2-diamine (174 mg), copper(I) iodide(116 mg), K₂CO₃ (338 mg) and THF(dry) (5 mL) was heated at 180° C. for 3h under microwave irradiation. The solid was removed by filtration, andthe filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, EtOAc/hexane) to give the titlecompound (72 mg) as an orange solid (mixture with1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, ca. 20% purity).

This product was subjected to the next reaction without furtherpurification.

MS (API+): [M+H]+ 343.1.

123b)1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A mixture of1-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(72 mg, mixture with 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, ca.20% purity), iodomethane (0.110 mL), and sodium hydride (70.8 mg) in DMF(1 ml) was stirred at 0° C. to room temperature overnight. The mixturewas quenched with water at room temperature and extracted with EtOAc.The organic layer was separated, washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, EtOAc/hexane) and column chromatography (NH silica gel,EtOAc/hexane) to give the title compound (7.40 mg) as a colorless oil.

MS (API+): [M+H]+ 371.3.

¹H NMR (300 MHz, CDCl₃) δ 1.46-1.55 (6H, m), 6.81 (1H, t, J=6.2 Hz),7.02 (1H, dd, J=7.6, 5.3 Hz), 7.12 (1H, s), 7.14-7.22 (1H, m), 7.29-7.41(2H, m), 7.48-7.59 (4H, m), 8.03 (1H, d, J=6.8 Hz), 8.17 (1H, dd, J=5.3,1.5 Hz).

Example 1241-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

124a) ethyl2-[4-(1-ethyl-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]imidazo[1,2-a]pyridine-3-carboxylate

The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (504mg),1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(302 mg) and NaH (67.3 mg) in DME (4 mL) was heated at 50° C. for 1 h.The mixture was heated at 200° C. for 3 h under microwave irradiation.The mixture was poured into sat. NaHCO₃, and the mixture was extractedwith EtOAc. The organic layer was separated, washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, EtOAc/hexane) to give the titlecompound (62.0 mg) as a white solid.

MS (API+): [M+H]+ 458.2.

124b)1-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of ethyl2-[4-(1-ethyl-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]imidazo[1,2-a]pyridine-3-carboxylate(62 mg) in EtOH (4 mL) was added sodium hydroxide (1.084 mL). Themixture was stirred at 50° C. for 2 h. Hydrochloric acid (2.168 mL) wasadded to the mixture, and the mixture was stirred at 60° C. for 10 h.The mixture was concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, EtOAc/hexane) to give thetitle compound (42.0 mg) as a colorless oil.

MS (API+): [M+H]+ 386.2.

¹H NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7.2 Hz), 2.40 (3H, s), 4.00(2H, q, J=7.2 Hz), 6.76-6.86 (1H, m), 7.10 (2H, s), 7.13-7.22 (1H, m),7.30-7.40 (2H, m), 7.51 (1H, d, J=9.1 Hz), 7.68-7.75 (2H, m), 7.88 (1H,s), 8.02 (1H, d, J=6.4 Hz).

Anal. Calcd for C₂₂H₁₉N₅O₂-0.5 H₂O: C, 67.06; H, 5.11; N, 17.77.

Found: C, 67.25; H, 5.16; N, 17.71.

Example 1257-ethyl-9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one

125a) 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole

Triethylamine (18 mL) was added to a mixture of2-chloro-1-methyl-1H-benzimidazole (7.2 g) and p-bromophenol (22.5 g) atroom temperature. The mixture was stirred at 120° C. for 6 h. Themixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with 1 N NaOH aq. andbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by column chromatography (NH silica gel, eluted with 10%-15%EtOAc in hexane) to give 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole(3.2 g) as colorless crystals.

MS (API+): [M+H]⁺ 304.92.

¹H NMR (300 MHz, CDCl₃) δ 3.73 (3H, s), 7.13-7.35 (5H, m), 7.50-7.61(3H, m).

125b)N-(diphenylmethylidene)-4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline

To a suspension of 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole (1.0 g),Pd₂(dba)₃ (0.076 g), sodium tert-butoxide (0.48 g) and xantphos (0.19 g)in dioxane (10 mL) was added benzophenone imine (0.83 ml), and themixture was stirred at 100° C. under Ar atmosphere for 6 h. Afterstirring at room temperature overnight, the mixture was poured intowater, and the mixture was extracted with AcOEt. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residualcrystals were washed with AcOEt to obtainN-(diphenylmethylidene)-4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline(0.81 g) as pale yellow crystals.

MS (API+): [M+H]⁺ 404.2.

¹H NMR (300 MHz, DMSO-d₆) δ 3.67 (3H, s), 6.74-6.82 (2H, m). 7.07-7.26(6H, m), 7.33-7.59 (8H, m), 7.64-7.71 (2H, m).

125c) 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline

To a suspension ofN-(diphenylmethylidene)-4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline(810 mg) in THF (10 mL) was added 1 N HCl aq (10 mL) at roomtemperature, and the mixture was stirred at room temperature for 1 h.The mixture was neutralized with sat. NaHCO₃ aq. and extracted withAcOEt. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, eluted with 5%-100% AcOEt in hexane) to give4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (440 mg) as colorlesscrystals.

MS (API+): [M+H]⁺ 240.2.

¹H NMR (300 MHz, DMSO-d₆) δ 3.68 (3H, s), 5.06 (2H, s), 6.55-6.64 (2H,m), 6.99-7.18 (4H, m), 7.30-7.43 (2H, m).

125d)6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine

To a solution of 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (0.30 g)and TEA (0.26 mL) in THF (15 mL) was added4,6-dichloro-5-nitropyrimidine (0.24 g) at room temperature, and themixture was stirred at room temperature for 2 h. The mixture was pouredinto water, and the mixture was extracted with AcOEt. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (dry charge,silica gel, eluted with 5%-50% AcOEt in hexane) to give6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine(0.24 g) as a yellow solid.

MS (API+): [M+H]⁺ 397.3.

¹H NMR (300 MHz, CDCl₃) δ 3.75 (3H, s), 7.17-7.26 (3H, m), 7.43-7.51(2H, m), 7.54-7.65 (3H, m), 8.48 (1H, s), 9.22 (1H, s).

125e)N⁴-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine

A mixture of6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine(240 mg) and 10% palladium on carbon (160 mg) in MeOH (10 mL) and THF(10 mL) was hydrogenated under balloon pressure at room temperatureovernight. To the mixture was added TEA (0.50 mL). The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography (silica gel, eluted with0%-5% MeOH in AcOEt) to giveN⁴-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine(80 mg) as a colorless solid.

MS (API+): [M+H]⁺ 333.4.

125f)9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one

A solution ofN⁴-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine(80 mg) and CDI (39 mg) in THF (20 mL) was refluxed for 3 h. CDI (39 mg)was added to the mixture. After refluxing overnight, the mixture wasconcentrated in vacuo. The residual solid was washed with AcOEt to give9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one(56 mg) as white crystals.

MS (API+): [M+H]⁺ 359.3.

125 g)7-ethyl-9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one

A mixture of9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one(56 mg), iodoethane (20 μL) and cesium carbonate (120 mg) in DMF (3 mL)was stirred at 50° C. for 4 h. The mixture was poured into water, andthe mixture was extracted with AcOEt. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidual crystals were recrystallized from AcOEt to give7-ethyl-9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one(40 mg) as white crystals.

MS (API+): [M+H]⁺ 387.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.34 (3H, t, J=7.2 Hz), 3.77 (3H, s), 4.01(2H, q, J=7.2 Hz), 7.11-7.24 (2H, m), 7.40-7.51 (2H, m), 7.58-7.66 (2H,m), 7.72-7.79 (2H, m), 8.64 (1H, s), 8.65 (1H, s).

mp 242-243° C.

Anal. Calcd for C₂₁H₁₈N₆O₂: C, 65.27; H, 4.70; N, 21.75. Found: C,64.99; H, 4.77; N, 21.70.

Example 1266-chloro-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

126a)3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Di-tert-butyl dicarbonate (17.05 mL) was added to a solution of2,5-dichloropyridin-3-amine (11.4 g) and NaHMDS (81 mL) in THF(dry) (200mL) at 0° C. The mixture was stirred at 0° C. under a dry atmosphere for1 h. The mixture was neutralized with 1N HCl at 0° C. and extracted withEtOAc. The organic layer was separated, washed with water and brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (NH silica gel, eluted with 0%-20% EtOAc inhexane) to give tert-butyl 2,5-dichloropyridin-3-ylcarbamate (15.6 g) ascolorless oil. The mixture of tert-butyl2,5-dichloropyridin-3-ylcarbamate (7.5 g), 4-benzyloxyanilinehydrochloride (10.08 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene(1.319 g), Pd₂(dba)₃ (1.044 g) and sodium tert-butoxide (6.57 g) intoluene (160 ml)-2-propanol (40.0 mL) was stirred at 100° C. under Arovernight. The reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, eluted with 0%-100%EtOAc in hexane) to give intermediate. To the intermediate in DMF (100ml) were added 2-iodopropane (5.69 mL) and NaH (2.280 g), and themixture was stirred at room temperature under a dry atmosphere (CaCl₂tube) for 1 h. The reaction mixture was diluted with MeOH andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-50% EtOAc in hexane) to give3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(560 mg) as a colorless solid.

MS (API+): [M+H]+ 394.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.41-1.57 (6H, m), 4.57-4.78 (1H, m), 5.18(2H, s), 7.09-7.21 (2H, m), 7.26-7.60 (7H, m), 7.81-8.08 (2H, m).

126b)6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(600 mg) and 10% Pd—C (162 mg) in EtOAc (50 mL) was hydrogenated underballoon pressure at room temperature for 1 h. The catalyst was removedby filtration and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, eluted with 0%-50%EtOAc in hexane) to give6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(200 mg) as a white solid.

MS (API+): [M+H]+ 304.1.

¹H NMR (300 MHz, DMSO-d₆) δ 1.38-1.65 (6H, m), 4.54-4.82 (1H, m),6.84-6.96 (2H, m), 7.30-7.41 (2H, m), 7.89-7.94 (1H, m), 7.93-7.98 (1H,m), 9.74 (1H, s).

126c)6-chloro-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (100 mg) was addedto a solution of6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(148 mg) and NaH (20.83 mg) in DMF (3 mL) at room temperature. Themixture was heated at 180° C. for 30 min under microwave irradiation.The reaction mixture was diluted with MeOH and concentrated in vacuo.The residue was purified by column chromatography (silica gel, elutedwith 0%-50% EtOAc in hexane) to give6-chloro-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(120 mg) as white crystals.

MS (API+): [M+H]+ 435.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.38-1.64 (6H, m), 3.77 (3H, s), 4.71 (1H,s), 7.15-7.28 (1H, m), 7.57-7.67 (2H, m), 7.69-7.86 (3H, m), 7.90-8.10(2H, m), 8.16-8.27 (1H, m).

Example 1276-(difluoromethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

127a)3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.72 g), Pd₂ dba₃ (0.21 g),2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.44 g) and KOH (1.10 g) in dioxane (15 ml,) and water (15 mL) wasstirred at 100° C. under Ar atmosphere for 3 h. After stirring at roomtemperature overnight, the mixture was acidified with 1 N HCl aq (11 mL)and diluted with water. The mixture was extracted with AcOEt. Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography (silica gel, elutedwith 10%-70% AcOEt in hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.31 g) as a pale yellow solid.

MS (API+): [M+H]⁺ 362.3.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7.2 Hz), 3.90 (2H, q, J=7.2Hz), 5.17 (2H, s), 7.08-7.17 (3H, m), 7.30-7.56 (8H, m), 9.58 (1H, brs).

127b)3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg), sodium chlorodifluoroacetate (253 mg), K₂CO₃ (172 mg), DMF (3ml), and water (0.60 ml) was refluxed overnight. The reaction mixturewas poured into water, and the mixture was extracted with AcOEt. Theextract was washed with brine, dried over MgSO₄, and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel, eluted with 10%-40% AcOEt in hexane) to give3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(110 mg) as a pale yellow oil.

MS (API+): [M+H]⁺ 412.1.

¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7.2 Hz), 3.98 (2H, q, J=7.2Hz), 5.10 (2H, s), 6.50 (1H, t, J=73.3 Hz), 7.04-7.17 (3H, m), 7.27-7.49(5H, m), 7.50-7.61 (2H, m), 7.92 (1H, d, J=2.3 Hz).

127c)6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(110 mg) and 10% palladium on carbon (40 mg) in MeOH (10 mL) washydrogenated under balloon pressure at room temperature for 2 h. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to give6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(86 mg) as a pale yellow oil.

MS (API+): [M+H]⁺ 322.3.

127d)6-(difluoromethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(62 mg) and6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H=imidazo[4,5-b]pyridin-2-one(86 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and themixture was stirred at 180° C. under microwave irradiation for 30 min.The mixture was partitioned between water and AcOEt. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (dry charge, NHsilica gel, eluted with 50%-100% AcOEt in hexane) and recrystallizedfrom AcOEt/hexane to give6-(difluoromethoxy)-1-ethyl-3-{4-[(3-methyl-3H=imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(56 mg) as white crystals.

MS (API+): [M+H]⁺ 453.4.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2 Hz), 3.77 (3H, s), 4.00(2H, q, J=7.2 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz), 7.24 (1H, t, J=74.0Hz), 7.59-7.67 (2H, m), 7.73-7.84 (4H, m), 7.92 (1H, d, J=2.3 Hz), 8.22(1H, dd, J=4.9, 1.5 Hz).

Anal, Calcd for C₂₂H₁₈N₆O₃F₂: C, 58.41; H, 4.01; N, 18.58. Found: C,58.30; H, 4.15; N, 18.43.

Mp: 195-197° C.

Example 1286-(2,2-difluoroethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

128a)3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2,2-Difluoroethyl trifluoromethanesulfonate (213 mg) was added to asolution of3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg) and potassium carbonate (229 mg) in DMF (5 ml) at roomtemperature. The mixture was stirred at ambient temperature under a dryatmosphere (CaCl₂ tube) for 3 h. The mixture was quenched with water atroom temperature and extracted with AcOEt. The organic layer wasseparated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, eluted with 15%-50% AcOEt in hexane) to give3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(301 mg) as colorless oil.

MS (API+): [M+H]⁺ 426.4

¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, d, J=7.3 Hz), 3.98 (2H, J=7.3 Hz),4.24 (2H, td, J=13.0, 4.0 Hz), 5.11 (2H, s), 6.10 (1H, tt, J=55.0, 4.0Hz), 6.96 (1H, d, J=2.6 Hz), 7.11 (2H, d, J=8.7 Hz), 7.28-7.48 (5H, m),7.56 (2H, d, J=8.7 Hz), 7.73 (1H, d, J=2.6 Hz).

128b)6-(2,2-difluoroethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg) and 10% Pd—C (37.5 mg) in EtOH (10 mL) was hydrogenated underballoon pressure at room temperature overnight. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give6-(2,2-difluoroethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneas a colorless solid. To a solution of this product and3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (153 mg) in DMF (5ml) was added sodium hydride (34.1 mg) at 100° C., and the mixture washeated at 180° C. for 30 min under microwave irradiation. The mixturewas quenched with water at room temperature and extracted with AcOEt.The organic layer was separated, washed with sat. NaHCO₃ aq. and brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (NH silica gel, eluted with 15%-50% AcOEt inhexane) to give6-(2,2-difluoroethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(264 mg) as a colorless solid. The solid was crystallized fromAcOEt-hexane.

MS (API+): [M+H]⁺ 467.3

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=7.2 Hz), 3.84 (3H, s), 4.01(2H, q, J=7.2 Hz), 4.26 (2H, td, J=13.0, 4.1 Hz), 6.12 (1H, tt, J=55.0,4.0 Hz), 6.98 (1H, d, J=2.6 Hz), 7.15 (1H, dd, J=7.9, 4.9 Hz), 7.56 (2H,d, J=8.7 Hz), 7.72-7.82 (2H, m), 7.88 (2H, d, J=9.0 Hz), 8.25 (1H, dd,J=4.9, 1.5 Hz).

Anal. Calcd for C₂₃H₂₀N₆O₃F₂-0.5H₂O: C, 58.10; H, 4.45; N, 17.68; F,8.15. Found: C, 58.20; H, 4.39; N, 17.65.

mp 171-172° C.

Example 1291-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

129a)3-[4-(benzyloxy)phenyl]-1-ethyl-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.144 mL) was added to asolution of3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(300 mg) and potassium carbonate (229 mg) in DMF (5 ml) at roomtemperature. The mixture was stirred at ambient temperature under a dryatmosphere (CaCl₂ tube) for 3 h. The mixture was quenched with water atroom temperature and extracted with AcOEt. The organic layer wasseparated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, eluted with 15%-50% AcOEt in hexane) to give3-[4-(benzyloxy)phenyl]-1-ethyl-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(308 mg) as colorless oil.

MS (API+): [M+H]⁺ 444.4

¹H NMR (300 MHz, CDCl₃) δ 1.40 (3H, d, J=7.2 Hz), 3.99 (2H, q, J=7.2Hz), 4.40 (2H, q, J=7.9 Hz), 5.11 (2H, s), 6.99 (1H, d, J=2.3 Hz), 7.11(2H, d, J=8.7 Hz), 7.28-7.49 (5H, m), 7.55 (2H, d, J=9.1 Hz), 7.74 (1H,d, J=2.6 Hz).

129b)1-Ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(305 mg) and 10% Pd—C (36.6 mg) in EtOH (10 mL) was hydrogenated underballoon pressure at room temperature overnight. The catalyst was removedby filtration and the filtrate was concentrated in vacuo to give1-ethyl-3-(4-hydroxyphenyl)-6-(2,2,2-trifluoroethoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-oneas colorless solid. To a solution of this product and3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (149 mg) in DMF (5mL), sodium hydride (33.1 mg) was added at 100° C. and the mixture washeated at 180° C. for 30 min under microwave irradiation. The mixturewas quenched with water at room temperature and extracted with AcOEt.The organic layer was separated, washed with sat. NaHCO₃ aq. and brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (NH silica gel, eluted with 15%-50% AcOEt inhexane) to give1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(262 mg) as colorless solid. The solid was crystallized fromAcOEt-hexane.

MS (API+): [M+H]⁺ 485.3

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=7.3 Hz), 3.85 (3H, s), 4.01(2H, q, J=7.3 Hz), 4.43 (2H, q, J=8.0 Hz), 7.02 (1H, d, J=2.3 Hz), 7.15(1H, dd, J=7.9, 4.9 Hz), 7.56 (2H, d, J=9.0 Hz), 7.75-7.82 (2H, m), 7.87(2H, d, J=9.4 Hz), 8.25 (1H, dd, J=4.9, 1.5 Hz).

Anal. Calcd for C₂₃H₁₉N₆O₃F₃-0.5H₂O: C, 55.98; H, 4.09; N, 17.03. Found:C, 55.88; H, 4.19; N, 16.94.

mp 178-179° C.

Example 1301-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

130a) methyl 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylate

To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylic acid(1.06 g) and K₂CO₃ (0.701 g) in DMF(dry) (10 mL) was added MeI (0.317ml). The mixture was stirred at room temperature for 3 h. The mixturewas directly purified by column chromatography (silica gel,EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc andhexane, ca. 75% purity).

MS (API+): [M+H]⁺ 224.0

130b) methyl2-{[4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylate

A mixture of 4-(benzyloxy)aniline (1010 mg), DIEA (1.771 mL) and methyl2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylate (1130 mg) in NMP (10mL) was stirred at 150° C. for 2 h and at 200° C. for 1 h undermicrowave irradiation. The mixture was poured into water, and themixture was extracted with EtOAc. The organic layer was separated,washed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography (silica gel,EtOAc/hexane) to give the title compound (225 mg).

MS (API+): [M+H]⁺ 403.3

130c)2-{[4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylicacid

To a mixture of methyl2-{[4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylate(255 mg) in MeOH (5 ml) was added 1N NaOH (2.54 mL), and the mixture wasstirred at 60° C. for 3 h. After MeOH was evaporated, to the water phasewas added 1N HCl (pH=ca. 2). The precipitate was collected by filtrationto give the title compound (221 mg).

MS (API+): [M+H]⁺ 389.3

130d)3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of2-{[4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylicacid (221 mg) and Et₃N (0.238 mL) in toluene (15 mL) was addeddiphenylphosphoryl azide (0.245 mL) at room temperature. The mixture wasstirred at 110° C. for 4 h. After cooling, the solvent was evaporated,and the precipitate was collected by filtration to give the to titlecompound (197 mg).

MS (API+): [M+H]⁺ 386.2

130e)3-[4-(benzyloxy)phenyl]-1-ethyl-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of NaH (40.9 mg),3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(197 mg) in DMF(dry) (3 mL) was added iodoethane (0.082 mL), and themixture was stirred at room temperature for 3 h. To the mixture wasadded sat. NaHCO₃ aq. and the mixture was extracted with EtOAc. Theorganic layer was separated, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the title compound (197 mg).

MS (API+): [M+H]⁺ 414.1

130f)1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1-ethyl-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(197 mg) and 10% palladium on carbon (50% wet, 68 mg) in MeOH (6.5 mL)and EtOAc (6.5 ml) was hydrogenated under balloon pressure at roomtemperature for 4 h. The solid was filtrated and washed with MeOH (10ml) to remove the catalyst. The filtrate was concentrated in vacuo togive the title compound (103 mg).

MS (API+): [M+H]⁺ 324.2

130 g)1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(81 mg) and1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(103 mg) in DMF(dry) (1.5 ml) was added NaH (19.12 mg), and the mixturewas stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30min under microwave irradiation. The mixture was poured into water, andthe mixture was extracted with EtOAc. The organic layer was separated,washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography (silica gel, EtOAc/hexane)to give the title compound as white crystals (62.2 mg).

MS (API+): [M+H]⁺ 455.3.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.0 Hz), 3.78 (3H, s),4.00-4.10 (2H, m), 7.21 (1H, dd, J=7.7, 5.1 Hz), 7.48 (1H, d, J=5.3 Hz),7.60-7.69 (2H, m), 7.72-7.78 (2H, m), 7.81 (1H, dd, J=7.9, 1.5 Hz), 8.17(1H, d, J=5.7 Hz), 8.22 (1H, dd, J=4.9, 1.5 Hz).

Anal. Calcd for C₂₂H₁₇N₆O₂F₃: C, 58.15; H, 3.77; N, 18.49. Found: C,58.05; H, 3.84; N, 18.33.

m.p. 244-246° C.

Example 1321-ethyl-6-fluoro-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

132a) N²-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine

A mixture of 4-(benzyloxy)aniline (2.26 g),2-chloro-5-fluoro-3-nitropyridine (2 g) and K₂CO₃ (3.13 g) in DMF (20mL) was stirred at 120° C. for 5 h, treated with water, and extractedwith AcOEt. The organic layer was dried over MgSO₄ and concentrated invacuo. The residue was suspended in IPE and collected by filtration. Thesolid obtained above was dissolved in EtOH (20 mL), and Pt/C (2 g) wasadded. Under H₂ atmosphere, the mixture was stirred for 1 h, filteredand evaporated. The residue was chromatographed on silica gel elutingwith Hexane/AcOEt to give the title compound (0.85 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.04 (2H, s), 5.39 (2H, s), 6.69-6.80 (1H,m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s).

132b)1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of N²-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine (0.85g) and 1,1′-carbonylbis(1H-imidazole) (0.45 g) in DME (10 mL) wasstirred at 100° C. for 4 h, and then Cs₂CO₃ (0.90 g) and1,1′-carbonylbis(1H-imidazole) (0.892 g) were added successively. Themixture was stirred at 100° C. for 10 min, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was dissolved in DMF (10 mL), andthen Cs₂CO₃ (3.58 g) and iodoethane (1.29 g) were added successively.The mixture was stirred at 100° C. for 2 h, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was dissolved in EtOH (30 mL), andPd/C (1.5 g) was added. Under H₂ atmosphere, the mixture was stirred atroom temperature for 30 min, filtered and evaporated. The residue waschromatographed on silica gel eluting with AcOEt/Hexane to give thetitle compound (0.52 g).

MS (API+): [M+H]⁺ 274.3.

132c)1-ethyl-6-fluoro-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred solution of1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at roomtemperature. The mixture was stirred at room temperature for 30 min, andthen 2-chloro-1-methyl-1H-benzimidazole (67.1 mg) was added. The mixturewas exposed to microwave irradiation at 180° C. for 30 min, treated withwater, and extracted with AcOEt. The organic layer was dried over MgSO₄and concentrated in vacuo. The residue was chromatographed on NH-silicagel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gavethe title compound (104 mg).

MS (API+): [M+H]⁺ 404.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2 Hz), 3.76 (3H, s), 3.98(2H, q, J=7.2 Hz), 7.09-7.25 (2H, m), 7.39-7.52 (2H, m), 7.56-7.64 (2H,m), 7.73-7.79 (2H, m), 7.83-7.91 (1H, m), 7.96-8.01 (1H, m).

Example 1331-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

133a) N²-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine

A mixture of 4-(benzyloxy)aniline (2.26 g),2-chloro-5-fluoro-3-nitropyridine (2 g) and K₂CO₃ (3.13 g) in DMF (20mL) was stirred at 120° C. for 5 h, treated with water, and extractedwith AcOEt. The organic layer was dried over MgSO₄ and concentrated invacuo. The residue was suspended in IPE and collected by filtration. Theobtained solid was dissolved in EtOH (20 mL), and Pt/C (2 g) was added.Under H₂ atmosphere, the mixture was stirred for 1 h, filtered andevaporated. The residue was chromatographed on silica gel eluting withHexane/AcOEt to give the title compound (0.85 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.04 (2H, s), 5.39 (2H, s), 6.69-6.80 (1H,m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s).

133b)1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of N²-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine (0.85g) and 1,1′-carbonylbis(1H-imidazole) (0.45 g) in DME (10 mL) wasstirred at 100° C. for 4 h, and then Cs₂CO₃ (0.90 g) and1,1′-carbonylbis(1H-imidazole) (0.892 g) were added successively. Themixture was stirred at 100° C. for 10 min, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was dissolved in DMF (10 ml), andthen Cs₂CO₃ (3.58 g) and iodoethane (1.29 g) were added successively.The mixture was stirred at 100° C. for 2 h, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was dissolved in EtOH (30 mL), andPd/C (1.5 g) was added. Under H₂ atmosphere, the mixture was stirred atroom temperature for 30 min, filtered and evaporated. The residue waschromatographed on silica gel eluting with AcOEt/Hexane to give thetitle compound (0.52 g).

MS (API+): [M+H]⁺ 274.3.

133c)1-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred solution of1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(100 mg) in DMF (4 ml) was added 60% sodium hydride (13.2 mg) at roomtemperature. The mixture was stirred at room temperature for 30 min, andthen 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (85 mg) wasadded. The mixture was exposed to microwave irradiation at 180° C. for30 min, treated with water, and extracted with AcOEt. The organic layerwas dried over MgSO₄ and concentrated in vacuo. The residue waschromatographed on NH-silica gel eluting with AcOEt/Hexane.Crystallization from AcOEt/Hexane gave the title compound (96 mg).

MS (API+): [M+H]⁺ 405.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.2 Hz), 3.77 (3H, s), 3.98(2H, q, J=7.2 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz), 7.57-7.66 (2H, m),7.72-7.91 (4H, m), 7.95-8.05 (1H, m), 8.18-8.24 (1H, m).

Example 1343-[4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

134a) ethyl N-(3-nitropyridin-2-yl)glycinate

To a solution of 2-chloro-3-nitropyridine (25.3 g) in EtOH (300 mL) wereadded ethyl 2-aminoacetate hydrochloride (28.7 g) and triethylamine(28.9 mL) at room temperature, and the mixture was refluxed for 1 day.The mixture was concentrated under reduced pressure. The residualcrystals were removed by filtration and washed with AcOEt. The filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, eluted with 20%-70% AcOEt in hexane).The residual crystals were removed by filtration and washed with IPE.The filtrate was concentrated under reduced pressure to give the titlecompound (26.9 g).

¹H NMR (300 MHz, CDCl₃) δ 1.30 (3H, t, J=7.2 Hz), 4.26 (2H, q, J=7.2Hz), 4.38 (2H, d, J=5.3 Hz), 6.72 (1H, dd, J=8.3, 4.5 Hz), 8.40 (1H, dd,J=4.5, 1.9 Hz), 8.44 (1H, dd, J=8.3, 1.9 Hz), 8.50 (1H, brs).

134b) ethyl N-(3-aminopyridin-2-yl)glycinate

A mixture of ethyl N-(3-nitropyridin-2-yl)glycinate (26 g) and 10%palladium on carbon (50% wet, 7.3 g) in AcOEt (250 mL) was hydrogenatedunder balloon pressure at room temperature for 8 h. The catalyst wasremoved by filtration. To the filtrate were added triethylamine (5.0 mL)and 10% palladium on carbon (50% wet, 7.3 g). The mixture washydrogenated under balloon pressure at room temperature overnight. Themixture was concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, eluted with 10%-50% AcOEtin hexane) to give the title compound (18 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.17 (3H, t, J=7.2 Hz), 3.98-4.13 (4H, m),4.72 (2H, s), 6.07 (1H, t, J=6.0 Hz), 6.38 (1H, dd, J=7.3, 5.1 Hz), 6.70(1H, dd, J=7.5, 1.5 Hz), 7.31 (1H, dd, J=4.9, 1.5 Hz).

134c) ethyl (2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetate

To a solution of ethyl N-(3-aminopyridin-2-yl)glycinate (18 g) in THF(200 mL) was added CDI (15 g) at room temperature, and the mixture wasstirred at room temperature overnight. The mixture was concentratedunder reduced pressure. The residual crystals were washed with AcOEt togive the title compound (5.5 g).

¹H NMR (300 MHz, CDCl₃) δ 1.30 (3H, t, J=7.2 Hz), 4.26 (2H, q, J=7.2Hz), 4.77 (2H, s), 7.02 (1H, dd, J=7.6, 5.3 Hz), 7.31 (1H, dd, J=7.6,1.1 Hz), 8.05 (1H, dd, J=5.3, 1.1 Hz), 9.70 (1H, brs).

134d) ethyl (2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)acetate

A mixture of ethyl(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetate (14.5 g) andphosphoryl chloride (100 mL) was stirred at 100° C. overnight. Themixture was poured into ice, neutralized with saturated sodiumbicarbonate solution and extracted with AcOEt. The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was diluted with AcOEt and insoluble crystals were removed byfiltration. The filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, eluted with10%-40% AcOEt in hexane) to give the title compound (5.46 g).

¹H NMR (300 MHz, CDCl₃) δ 1.29 (3H, t, J=7.2 Hz), 4.26 (2H, J=7.2 Hz),5.07 (2H, s), 7.23-7.32 (1H, m), 7.99 (1H, dd, J=8.1, 1.5 Hz), 8.36 (1H,dd, J=4.9, 1.5 Hz).

134e) ethyl{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}acetate

A mixture of ethyl (2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)acetate (2.8g) and 4-nitroaniline (1.6 g) was stirred at 150° C. for 1 h to give thetitle compound (4.0 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (3H, t, J=7.2 Hz), 4.18 (2H, q, J=7.2Hz), 5.21 (2H, s), 7.20 (1H, dd, J=7.6, 4.9 Hz), 7.85 (1H, d, J=7.6 Hz),8.06-8.20 (3H, m), 8.23-8.34 (2H, m), 9.98 (1H, brs).

134f) 2-{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethanol

To a suspension of ethyl{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}acetate (3.6 g)in THF (120 mL) was added lithium borohydride (0.77 g) at roomtemperature, and the mixture was refluxed for 2 h. The mixture wascooled to room temperature, quenched with water and extracted withAcOEt. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, eluted with 50%-100% AcOEt in hexane) togive the title compound (2.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.80 (2H, t, J=5.5 Hz), 4.45 (2H, t, J=5.5Hz), 7.17 (1H, dd, J=7.6, 4.9 Hz), 7.82 (1H, dd, J=7.6, 1.1 Hz),8.06-8.19 (3H, m), 8.23-8.33 (2H, m).

134 g)1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridine

To a solution of2-{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethanol (2.2g) and triethylamine (10 mL) in THF (100 ml) was added methanesulfonylchlorode (1.1 mL) at 0° C., and the mixture was stirred at 0° C. for 2h. The mixture was poured into water and extracted with AcOEt. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. A mixture of the residue andpotassium carbonate (3.1 g) in NMP (30 mL) was stirred at 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water. The formed crystals were collected by filtration to give thetitle compound (1.7 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.40-4.51 (2H, m), 4.64-4.75 (2H, m), 7.16(1H, dd, J=8.0, 4.9 Hz), 7.83 (1H, d, J=8.0 Hz), 8.03 (2H, d, J=9.1 Hz),8.09 (1H, d, J=4.9 Hz), 8.35 (2H, d, J=9.1 Hz).

134 h)4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)aniline

A mixture of1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridine(1.7 g) and 10% palladium on carbon (50% wet, 1.0 g) in MeOH (150 ml)was hydrogenated under balloon pressure at room temperature for 1 day.The catalyst was removed by filtration and the filtrate was concentratedunder reduced pressure to give the title compound (1.2 g).

MS (API+): [M+H]⁺ 252.4.

134i)3-[4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The mixture of 2-chloro-3-nitropyridine (189 mg),4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)aniline(300 mg) and DIPEA (1.0 mL) in DMSO (5 mL) was stirred at 120° C. for 4h. The mixture was diluted with AcOEt and THF, and washed with water.The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. A mixture of the residue and 10% palladium on carbon(50% wet, 0.20 g) in MeOH (30 mL) was hydrogenated under balloonpressure at room temperature for 1 day. The catalyst was removed byfiltration and the filtrate was concentrated under reduced pressure.

A solution of the residue and CDI (193 mg) in THF (15 mL) was refluxedfor overnight. To the mixture was added CDI (193 mg), and the mixturewas refluxed for 5 h. After cooling to room temperature, the formedprecipitate was collected by filtration to give the title compound (165mg).

¹H NMR (300 MHz, DMSO-d₅) δ 4.38-4.49 (2H, m), 4.58-4.70 (2H, m),7.05-7.14 (2H, m), 7.40 (1H, dd, J=7.9, 1.5 Hz), 7.67 (2H, d, J=9.1 Hz),7.74 (1H, dd, J=7.7, 1.3 Hz), 7.91-7.99 (3H, m), 8.02 (1H, dd, J=4.9,1.5 Hz), 11.36 (1H, s).

134j)3-[4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(165 mg), iodoethane (0.054 mL) and cesium carbonate (291 mg) in DMF (3mL) was stirred at 50° C. for 6 h. The mixture was poured into water andextracted with AcOEt. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidual crystals were dissolved in THF, and the solution was filteredthrough NH-silica gel. The filtrate was concentrated under reducedpressure. The residual crystals were recrystallized from EtOH to givethe title compound (94 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2 Hz), 3.98 (2H, q, J=7.2Hz), 4.37-4.49 (2H, m), 4.57-4.71 (2H, m), 7.10 (1H, dd, J=7.9, 4.9 Hz),7.17 (1H, dd, J=7.7, 5.1 Hz), 7.62-7.71 (3H, m), 7.74 (1H, dd, J=7.7,1.3 Hz), 7.91-8.06 (4H, m).

MS (ESI+): [M+H]⁺ 398.1.

mp 255-256° C.

Anal. Calcd for C₂₂H₁₉N₇O: C, 66.49; H, 4.82; N, 24.67. Found: C, 66.24;H, 4.85; N, 24.41.

Example 1351,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

135a)3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

MeI (0.377 mL) was added to a solution of3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.0 g) and NaH (0.362 g) in DMF (20 mL) at 20° C. The mixture wasstirred at 20° C. under a dry atmosphere for 1 h. The mixture wasdiluted with sat. NaHCO₃ at 20° C. and extracted with EtOAc. The organiclayer was separated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo to give3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.0 g). This product was subjected to the next reaction without furtherpurification.

135b)3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2.0 g) and 10% Pd—C (0.308 g) in DMF (10 mL)-EtOAc (100 mL) washydrogenated under balloon pressure at 20° C. for 1 h. The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography (NH silica gel, elutedwith 50%-100% EtOAc in hexane) to give3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(1.30 g) as a light brown solid. This product was subjected to the nextreaction without further purification.

135c)1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) was addedto a solution of3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(725 mg) and potassium tert-butoxide (351 mg) in DMA (4 ml) at 20° C.The mixture was stirred at 150° C. under a dry atmosphere for 30 min.The reaction mixture was diluted with MeOH and concentrated in vacuo.The residue was purified by column chromatography (NH silica gel, elutedwith 0%-50% EtOAc in hexane) to give1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(150 mg) as colorless crystals.

MS (API+): [M+H]⁺ 387.1.

¹H NMR (300 MHz, DMSO-d₆) δ 2.59-2.69 (3H, s), 3.66 (3H, s), 3.78 (3H,s), 6.91-7.06 (1H, m), 7.13-7.28 (1H, m), 7.56-7.66 (2H, m), 7.70-7.76(2H, m), 7.77-7.83 (1H, m), 7.83-7.89 (1H, m), 8.15-8.28 (1H, m).

Example 1361-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide

Triisopropylsilyl chloride (2.384 mL) was added to a solution of1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(2 g) and NaH (0.594 g) in DMF (20 ml) at 20° C. The mixture was stirredat 20° C. under a dry atmosphere (CaCl₂ tube) for 1 h. The mixture waspoured into sat. NaHCO₃ at 0° C. and extracted with EtOAc. The organiclayer was separated, washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-25% EtOAc in hexane) to give1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(4.0 g) as light brown crystals.

Trifluoroacetic anhydride (3.92 mL) was added to a suspenstion of1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(4 g) and urea hydrogen peroxide (2.74 g) in EtOAc (20 mL) at 0° C. Themixture was stirred at room temperature under a dry atmosphere (CaCl₂tube) overnight. The mixture was neutralized with sat. NaHCO₃ at 0° C.and extracted with EtOAc. The organic layer was separated, washed withwater and brine, dried over MgSO₄ and concentrated in vacuo. The residuewas purified by column chromatography (NH silica gel, eluted with0%-100% EtOAc in hexane) to give1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide (250 mg) as colorless crystals.

Tetrabutylammonium fluoride (0.566 mL) was added to a solution of1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide (250 mg) in THF (5 mL) at room temperature. The mixture wasstirred at room temperature under a dry atmosphere (CaCl₂ tube) for 30min. The reaction mixture was concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 0%-100% EtOAcin hexane) to give1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide (170 mg) as a colorless solid.3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (126 mg) was addedto a solution of1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide (170 mg) and NaH (23.83 mg) in DMA (1 mL) at room temperature.The mixture was stirred at 150° C. under a dry atmosphere (CaCl₂ tube)for 30 min. The reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography (NH silica gel, eluted with50%-100% EtOAc in hexane) to give1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide as colorless crystals.

MS (API+): [M+H]⁺ 417.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.40 (3H, m), 2.58 (3H, s), 3.77 (3H,s), 4.01-4.19 (2H, m), 6.96-7.05 (1H, m), 7.15-7.29 (1H, m), 7.40-7.57(4H, m), 7.75-7.90 (2H, m), 8.15-8.29 (1H, m).

Example 137(1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)methylacetate

The mixture of1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide (500 mg) in acetic anhydride (10 mL) was stirred at 80° C. undera dry atmosphere (CaCl₂ tube) for 2 h. The reaction mixture wasconcentrated in vacuo. The residue was purified by column chromatography(silica gel, eluted with 0%-30% EtOAc in hexane) to give[1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (300 mg) as colorless oil.

Tetrabutylammonium fluoride (1.241 ml) was added to a solution of[1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (300 mg) in THF(dry) (1 ml) at room temperature. The mixture wasstirred at room temperature under a dry atmosphere (CaCl₂ tube) for 30min. The reaction mixture was concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with 20%-100%EtOAc in hexane) to give[1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (170 mg) as a white solid.

3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (110 mg) was addedto a solution of[1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (170 mg) and potassium tert-butoxide (69.9 mg) in DMA (1 mL) atroom temperature. The mixture was stirred at 100° C. under a dryatmosphere (CaCl₂ tube) for 30 min. The reaction mixture wasconcentrated in vacuo. The residue was purified by column chromatography(NH silica gel, eluted with 0%-100% EtOAc in hexane) to give(1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)methylacetate (10 mg) as colorless crystals.

MS (API+): [M+H]⁺ 459.2.

¹H NMR (300 MHz, DMSO-d₆) δ1.28-1.41 (3H, m), 2.14 (3H, s), 3.78 (3H,s), 4.00-4.18 (2H, m), 5.40 (2H, s), 7.15-7.26 (2H, is m), 7.56-7.87(5H, m), 7.95-8.04 (1H, m), 8.12-8.28 (1H, m).

Example 1381-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred mixture of[1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (150 mg) and EtOH (3 ml) was added 1 N NaOH (2 mL) at 0° C. Themixture was stirred at 0° C. for 30 min, treated with saturated NH₄Clsolution, and extracted with AcOEt. The organic layer was dried overMgSO₄ and concentrated in vacuo. The residue was dissolved in DMA (4 mL)and KOtBu (52 mg) was added at room temperature. The mixture was stirredfor 2 min, and then3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (97 mg) was added.The mixture was stirred at 150° C. for 30 min, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was chromatographed on NH-silica geleluting with AcOEt/MeOH=20/1. The product was crystallized fromAcOEt/Hexane to give1-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(46 mg).

MS (API+): [M+H]⁺ 417.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.2 Hz), 3.78 (3H, s), 4.13(2H, q, J=7.2 Hz), 4.80 (2H, d, J=5.5 Hz), 5.67 (1H, t, J=5.5 Hz),7.14-7.26 (2H, m), 7.59-7.68 (2H, m), 7.71-7.87 (3H, m), 7.97 (1H, d,J=5.3 Hz), 8.17-8.28 (1H, m).

Alternative route for1-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneis described below.

138a)1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred mixture of1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(10 g) and 1H-imidazole (3.79 g) in DMF (100 mL) was addedtriisopropylsilyl chloride (9.54 mL) at 0° C. The mixture was stirred atroom temperature for 3 days, treated with water, and extracted withAcOEt. The organic layer was dried over MgSO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography(AcOEt/Hexane=1/10) to give the title compound (11.5 g).

MS (API+): [M+H]⁺ 426.2.

¹H NMR (300 MHz, DMSO-d₆) δ1.05-1.19 (18H, m), 1.23-1.37 (6H, m), 2.59(3H, s), 4.08 (2H, d, J=7.2 Hz), 6.89-7.05 (3H, m), 7.46 (2H, d, J=8.7Hz), 7.80-7.86 (1H, m).

138b)1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide

To a stirred mixture of1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(5 g) and urea hydrogen peroxide (2.32 g) in CH₂Cl₂ (50 mL) was addedtrifluoroacetic anhydride (3.32 mL) at 0° C. The mixture was stirred atroom temperature for 12 h, and treated with saturated NaHCO₃ solution.The organic layer was separated and the aqueous layer was extracted withAcOEt. The organic layer was combined, dried over MgSO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(NH, AcOEt) to give the title compound (1.0 g).

MS (API+): [M+H]⁺ 442.3.

¹H NMR (300 MHz, DMSO-d₆) δ0.99-1.17 (18H, m), 1.22-1.36 (6H, m), 2.56(3H, s), 4.06 (2H, q, J=7.2 Hz), 6.82-6.91 (2H, m), 6.92-7.00 (1H, m),7.14-7.24 (2H, m), 7.73 (1H, d, J=6.8 Hz).

138c)[1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate

A mixture of1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide (1 g) and Ac₂O (20 mL) was stirred at 80° C. for 2 h, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (AcOEt/hexane) to give the title compound (0.49 g).

MS (API+): [M+H]⁺ 484.3.

5 ¹H NMR (300 MHz, DMSO-d₆) δ1.03-1.15 (18H, m), 1.24-1.39 (6H, m), 2.13(3H, s), 4.03 (2H, q, J=7.2 Hz), 5.37 (2H, s), 6.91-7.09 (2H, m),7.07-7.29 (1H, m), 7.45-7.50 (2H, m), 7.95 (1H, d, J=5.3 Hz).

138d)[1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate

To a stirred solution of[1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (480 mg) in THF (5 ml) was added a solution oftetrabutylammonium fluoride (778 mg) in THF (2 mL) at 0° C. The mixturewas stirred at 0° C. for 30 min, treated with water, and extracted withAcOEt. The organic layer was dried over MgSO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography(AcOEt/Hexane=1/1) to give the title compound (276 mg).

MS (API+): [M+H]⁺ 328.1.

¹H NMR (300 MHz, DMSO-d₆) δ1.30 (3H, t, J=7.2 Hz), 2.12 (3H, s), 4.03(2H, q, J=7.2 Hz), 5.36 (2H, s), 6.80-6.95 (2H, m), 7.12 (1H, d, J=5.3Hz), 7.28-7.41 (2H, m), 7.93 (1H, d, J=5.3 Hz), 9.71 (1H, s).

138e)1-ethyl-7-(hydroxymethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a stirred mixture of[1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methylacetate (150 mg) and EtOH (3 mL) was added 1N NaOH (2 ml) at 0° C. Themixture was stirred at 0° C. for 30 min, treated with saturated NH₄Clsolution, and extracted with AcOEt. The organic layer was dried overMgSO₄ and concentrated in vacuo. The residue was dissolved in DMA (4 ml)and KOtBu (52 mg) was added at room temperature. The mixture was stirredfor 2 min, and then3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (97 mg) was added.The mixture was stirred at 150° C. for 30 min, treated with water, andextracted with AcOEt. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (NH, AcOEt/MeOH=20/1) and crystallized from AcOEt/hexaneto give the title compound (46 mg).

MS (API+): [M+H]⁺ 417.2.

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.2 Hz), 3.78 (3H, s), 4.13(2H, q, J=7.2 Hz), 4.80 (2H, d, J=5.5 Hz), 5.67 (1H, t, J=5.5 Hz),7.14-7.26 (2H, m), 7.59-7.68 (2H, m), 7.71-7.87 (3H, m), 7.97 (1H, d,J=5.3 Hz), 8.17-8.28 (1H, m).

Example 1391-ethyl-3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

139a) 1-(5-methylpyridin-2-yl)-2H-indazol-5-amine

To a stirred solution of 5-nitro-1H-indazole (500 mg) in DMF (10 mL) wasadded 60% sodium hydride (129 mg) at room temperature. The mixture wasstirred for 30 min, and 5-bromo-2-chloropyridine (649 mg) was added. Themixture was exposed to microwave irradiation at 230° C. for 1 h, treatedwith sat. ammonium chloride solution, and extracted with AcOEt. Theorganic layer was dried over MgSO₄ and concentrated in vacuo. Theresidue was chromatographed on silica gel eluting with AcOEt/Hexane togive a mixture of 1-(5-bromopyridin-2-yl)-5-nitro-1H-indazole and2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole.

To the mixture of 1-(5-bromopyridin-2-yl)-5-nitro-1H-indazole and2-(5-bromopyridin-2-yl)-5-nitro-2H-indazole were added methylboronicacid (141 mg), Pd(Ph₃P)₄ (91 mg), DME (3 ml) and a solution of Cs₂CO₃(766 mg) in H₂O (1 mL), successively. The mixture was exposed tomicrowave irradiation 140° C. for 1 h, treated with water, and extractedwith AcOEt. The organic layer was dried over MgSO₄ and concentrated invacuo to give a mixture of 1-(5-methylpyridin-2-yl)-5-nitro-1H-indazoleand 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole.

The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-1H-indazole and2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20ml), and 10% Pd/C (250 mg) was added. Under H₂ atmosphere, the mixturewas stirred at room temperature for 12 h, filtered and concentrated invacuo. The residue was chromatographed on silica gel eluting withAcOEt/Hexane to give the title compound (61 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (3H, s), 5.04 (2H, s), 6.58 (1H, d,J=1.9 Hz), 6.86 (1H, dd, J=9.1, 1.9 Hz), 7.44 (1H, d, J=9.1 Hz),7.75-7.90 (1H, m), 7.95-8.06 (1H, m), 8.35 (1H, d, J=2.3 Hz), 8.72 (1H,d, J=0.8 Hz).

139b)3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Under argon atmosphere, a mixture of1-(5-methylpyridin-2-yl)-2H-indazol-5-amine (60 mg), tert-butyl2-chloropyridin-3-ylcarbamate (67.3 mg), Pd₂(dba)₃ (24.5 mg), Xantphos(31.0 mg) and sodium tert-butoxide (28.3 mg) in 2-propanol (2 mL) andtoluene (0.5 mL) was stirred at 90° C. for 24 h, treated with water andextracted with EtOAc. The organic layer was separated, dried over MgSO₄and concentrated in vacuo. The residue was chromatographed on silica geleluting with AcOEt/Hexane to give the title compound as white crystals(31 mg).

MS (API+): [M+H]⁺ 343.3.

139c)1-ethyl-3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A mixture of3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(31 mg) and iodoethane (15.5 mg) in DMF (2 mL) was stirred at 50° C. for3 h, treated with water, and extracted with AcOEt. The organic layer wasdried over MgSO₄ and concentrated in vacuo. The residue waschromatographed on silica gel eluting with AcOEt/Hexane. The product wascrystallized from AcOEt/Hexane to give the title compound as whitecrystals (5.4 mg).

MS (API+): [M+H]⁺ 371.0.

Example compounds shown in the following Tables 1-12 (includingcompounds shown in the above-mentioned Examples) were obtained by amethod known per se, or a method similar to those in the above-mentionedExamples, or a method analogous thereto.

Particularly, the Example compounds described in the column under“Referred Example No.” in Tables 1-12 were produced according to thesynthetic method described in the Referred Example.

In addition, the compound of each Example in Tables 1-12 was synthesizedusing the compound described in the column under “Raw material”.

TABLE 1 Ex- am- Reffered Raw ple Example Material, No. MS STRUCTURE SALTName No. Conditions 14 345  

9-[4-(1,3- benzoxazol-2- ylamino)phenyl]- 7,9-dihydro-8H- purin-8-one 14-chloro-5- nitropyrimidine 15 383  

3-[4-(3,4- dihydropyrimido [1,2- a]benzimidazol- 1(2H)- yl)phenyl]-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 2 1,3- dibromopropane 16 397  

3-[4-(2,3,4,5- tetrahydro-1H- [1,3]diazepino[1, 2- a]benzimidazol-1-yl)phenyl]-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one 21,4-diiodobutane 17 358  

3-[4-(1,3- benzoxazol-2- ylamino)phenyl]- 1-methyl-1,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one 12c, 3, 1c, 1a 12c) tert-butyl 2-chloropyridin-3- ylcarbamate, 4- nitroaniline 18 502.1

1-ethyl-3-{4-[(1- {[2- (trimethylsilyl) ethoxy)methyl]- 1H-benzimidazol-2- yl)oxy]phenyl}- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 12d 3-{4-[(1-{[2- (trimethylsilyl) ethoxy]methyl}-1H-benzimidazol- 2- yl)oxy]phenyl}- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 19 386.2

1-ethyl-3-{4-[(1- methyl-1H- benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 3 3-[4-(1H- benzimidazol-2-yloxy)phenyl]-1- ethyl-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-onehydrochloride 20 371.3

3-[4-(1H- benzimidazol-2- ylamino)phenyl]- 1-ethyl-1,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one — 3-(4- aminophenyl)-1- ethyl-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one, phenylenedia- mine, 1,1′-thiocarbonyldi- imidazole, N,N′- dicyclohexyl- carbodiimide

TABLE 2 Ex- am- Reffered ple Example No. MS STRUCTURE SALT Name No. RawMaterial 21 400.1

3-{4-[(1-methyl-1H- benzimidazol-2- yl)oxy]phenyl}-1-(1-methylethyl)-1,3- dihydro- 2H-imidazo[4,5- b]pyridin-2-one  3 3-[4-(1H-benzimidazol-2- yloxy)phenyl]-1-(1- methylethyl)-1,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one 22 386.0

HCl 3-[4-(1H- benzimidazol- 2-yloxy)phenyl]-1-(1- methylethyl)-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one hydrochloride 3, 1c, 7e, 8 3)3-[4- (benzyloxy)phenyl]- 1,3-dihydro-2H- imidazo[4,5-b]pyridin- 2-one,2-iodopropane 23 426.1

HCl 3-[4-(1H- benzimidazol- 2-yloxy)phenyl]-1- (2,2,2-trifluoroethyl)-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2- one hydrochloride 222-lodo-1,1,1- trifluoroethane 24 397.1

3-[4-(2,3-dihydro-1H- imidazo[1,2- a]benzimidazol-1- yl)phenyl]-1-ethyl-1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 12d 3-[4-(2,3-dihydro-1H-imidazo[1,2- a]benzimidazol-1- yl)phenyl]-1,3- dihydro-2H-imidazo[4,5-b]pyridin- 2-one 25 455.3

ethyl {3-[4-(2,3- dihydro-1H- imidazo[1,2- a]benzimidazol-1-yl)phenyl]-2-oxo- 2,3-dihydro-1H- imidazo[4,5- b]pyridin-1- yl}acetate 3 ethyl bromoacetate 26 413  

3-[4-(2,3-dihydro- 1H-imidazo[1,2- a]benzimidazol-1- yl)phenyl]-1-(2-hydroxyethyl)-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one — ethyl{3-[4-(2,3- dihydro-1H- imidazo[1,2- a]benzimidazol-1- yl)phenyl]-2-oxo-2,3-dihydro- 1H-imidazo[4,5- b]pyridin-1- yl}acetate, LAH 27 390.4

1 -ethyl-3-{4-[(6- fluoro-1,3- benzoxazol-2- yl)amino]phenyl)-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 17 2-chloro-5-fluorobenzoxazol

TABLE 3 Ex- am- Reffered ple Example No. MS STRUCTURE SALT Name No. RawMaterial 28 404.3

1-ethyl-3-{4- [(6-fluoro-1,3- benzoxazol-2- yl)(methyl) amino]phenyl}-1,3-dihydro-2H- imidazo[4,5- b)pyridin-2-one 3 1-ethyl-3- {4-[(6-fluoro-1,3-benzoxazol-2- yl)amino]phenyl}- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 29 422.3

3-{4-[(5,6- difluoro-1-methyl- 1H-benzimidazol-2- yl)oxy]phenyl}-1-ethyl-1,3- dihydro-2H- imidazo[4,5- b]pyridin- 2-one 7e 2-chloro-5,6-difluoro-1-methyl- 1H-benzimidazole, 1-ethyl-3-(4- hydroxyphenyl)-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one, NaH, DMF, microwave, 200°C. 30 444.4

ethyl 2-[4-(1- ethyl-2-oxo- 1,2-dihydro-3H- imidazo[4,5- b]pyridin-3-yl)phenoxy]imidazo [1,2-a]pyridine-3- carboxylate 7e ethyl 2-chloroimidazo[1,2- a]pyridine-3- carboxylate 31 372.4

1-ethyl-3-[4- (imidazo[1,2- a]pyridin-2- yloxy)phenyl]-1,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one — ethyl 2-[4-(1- ethyl-2-oxo-1,2-dihydro-3H- imidazo[4,5- b]pyridin-3- yl)phenoxy]imi- dazo[1,2-a]pyridine-3- carboxylate, DMF, 200° C. 32 404

1-ethyl-3-{4- [(6-fluoro-1-methyl- 1H-benzimidazol-2-yl)oxy]phenyl}-1,3- dihydro 2H-imidazo[4,5- b]pyridin-2-one 292-chloro-6-fluoro- 1-methyl-1H- benzimidazole (US2003/166637),1-ethyl-3-(4- hydroxyphenyl)- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 33 404

1-ethyl-3-{4- [(5-fluoro-1-methyl- 1H-benzimidazol-2-yl)oxy]phenyl)-1,3- dihydro- 2H-imidazo[4,5- b]pyridin-2-one 292-chloro-5-fluoro-1- methyl-1H- benzimidazole, 1-ethyl-3-(4-hydroxyphenyl)- 1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 34 430.1

1-(2-hydroxy-2- methylpropyl)-3- {4-[(1-methyl-1H- benzimidazol-2-yl)oxy]phenyl}- 1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 25, 1c, 2925) 3-[4- (benzyloxy)phenyl]- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 29) 2-chloro-1-methyl- 1H-benzimidazole, MeMgBr

TABLE 4 Ex- am- Reffered ple Example No. MS STRUCTURE SALT Name No. RawMaterial 35 402.1

1-(2-hydroxyethyl)- 3-{4-[(1-methyl-1H- benzimidazol-2-yl)oxy]phenyl}-1,3- dihydro-2H- imidazo[4,5-b]pyridin- 2-one 25, 1c, 29,26 25) 3-[4- (benzyloxy)phenyl]- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 29) 2-chloro-1- methyl-1H- benzimidazole 36 384.2

1-ethyl-3-[4- (quinoxalin-2- yloxy)phenyl]-1,3- dihydro-2H-imidazo[4,5-b]pyridin- 2-one 7e 2-chloroquinoxaline, 1-ethyl-3-(4-hydroxyphenyl)- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 37 428.5

3-{4-[(1-butyl- 1H-benzimidazol-2- yl)oxy]phenyl}- 1-ethyl-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 7f 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl) ethoxy]methyl}-1H- benzimidazol- 2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 38 414.4

3-{4-[(1-acetyl-1H- benzimidazol-2- yl)oxy]phenyl}-1- ethyl-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one — 3-[4-(1H- benzimidazol-2-yloxy)phenyl]-1- ethyl-1,3- dihydro-2H- imidazo[4,5- b]pyridin- 2-one,acetyl chloride, triethyl amine,THF 39 416.5

1-ethyl-3-(4-{[1-(2- hydroxyethyl)-1H- benzimidazol-2-yl]oxy}phenyl)-1,3- dihydro-2H- imidazo[4,5-b]pyridin- 2-one 25, 263-[4-(1H- benzimidazol-2- yloxy)phenyl]-1- ethyl-1,3- dihydro-2H-imidazo[4,5-]pyridin- 2-one 40 444.4

1-ethyl-3-(4-{[1-(2- hydroxy-2- methylpropyl)-1H- benzimidazol-2-yl]oxy}phenyl)-1,3- dihydro-2H- imidazo[4,5-b]pyridin- 2-one 39 ethyl{2-[4-(1- ethyl-2-oxo- 1,2-dihydro-3H- imidazo[4,5- b]pyridin-3-yl)phenoxy]-1H- benzimidazol-1- yl}acetate, MeMgBr, THF 41 386.3

HCl 3-[4-(1H- benzimidazol-2- yloxy)-3- methylphenyl]-1-ethyl-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one hydrochloride 7a, 7b,7c, 22 4-(benzyloxy)- 3-methylaniline

TABLE 5 Ex- am- Reffered ple Example No. MS MOLSTRUCTURE SALT NAME No.Raw Material 42 400.1

1-ethyl-3-{3-methyl- 4-[(1-methyl-1H- benzimidazol-2-yl)oxy]phenyl}-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2- one  33-[4-(1H- benzimidazol- 2-yloxy)-3- methylphenyl]- 1-ethyl-1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 43 404.3

1-ethyl-3-{3-fluoro- 4-[(1-methyl-1H- benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H imidazo[4,5- b]pyridin-2- one 7a, 7b, 7c, 3, 1c, 7e 7a)4-(benzyloxy)- 3-fluoroaniline 7e) 1-methyl-2- (methylsulfonyl)-1H-benzimidazole 44 371.4

1-[4-(2-oxo-3- phenylimidazolidin- 1-yl)phenyl]-1,3- dihydro-2H-pyrrolo[2,3-b]pyridin- 2-one 5a then 5a 5a) 1,4-diiodobenzene,1-phenylimidazolidin- 2-one, then 5a) 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin- 2-one 45 329.4

1-[4-(2,3-dihydro- 1H-pyrrolo[2,3- b]pyridin-1- yl)phenyl]-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin- 2-one 44 1,4-diiodobenzene,2,3-dihydro-1H- pyrrolo[2,3- b]pyridine 46 373.3

1-ethyl-3-[4- ([1,2,4]triazolo[1,5- a]pyridin-2- yloxy)phenyl]-1,3-dihydro-2H- imidazo[4,5-b]pyridin- 2-one 29 1-ethyl-3-(4-hydroxyphenyl)-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one, 2-chloro-[1,2,4]triazolo[1,5- a]pyridine 47 390.4

1-ethyl-3-{4-[(7- fluoro-1H- benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin- 2-one 29, 8 1-ethyl-3-(4-hydroxyphenyl)-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one,4-fluoro-2- (methylsulfonyl)-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-benzo[d]imidazole 48 411.4

1-ethyl-3-[1-(1- methyl-1H- benzimidazol-2-yl)- 2,3-dihydro-1H-indol-5-yl]-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one  3 3-[1-(1H-benzimidazol-2-yl)- 2,3-dihydro-1H- indol-5-yl]-1- ethyl-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

TABLE 6 Ex- am- Reffered ple Example No. MS MOLSTRUCTURE SALT NAME No.Raw Material 49 386.3

3-[4-(1H- benzimidazol-2- yloxy)-2- methylphenyl]-1- ethyl-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyloxy)-2-methylaniline 50 412.3

3-[4-(1H- benzimidazol-2- yloxy)-2- methylphenyl]-1-(cyclopropylmethyl)- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 49(bromomethyl) cyclopropane 51 400.4

1-ethyl-3-{2- methyl-4-[(1-methyl- 1H-benzimidazol-2-yl)oxy]phenyl)-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one  33-[4-(1H- benzimidazol-2- yloxy)-2- methylphenyl]- 1-ethyl-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 52 432.1

3-[4-(1-benzyl-2 methyl-1H- benzimidazol-4- yl)phenyl]-1,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one  8 3-[4-(1-benzyl-2- methyl-1H-benzimidazol-4- yl)phenyl]-1- ([2-(trimethylsilyl) ethoxy]methyl)-1,3-dihydro-2H- imidazo[4,5-b]pyridin- 2-one 53 460.1

3-[4-(1-benzyl-2- methyl-1H- benzimidazol-4- yl)phenyl]-1-ethyl-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one 12d 3-[4-(1-benzyl-2-methyl-1H- benzimidazol-4- yl)phenyl]-1,3- dihydro-2H-imidazo[4,5-b]pyridin- 2-one 54 370.1

1-ethyl-3-[4-(2- methyl-1H- benzimidazol-4- yl)phenyl]- 1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 1c 3-[4-(1-benzyl-2- methyl-1H-benzimidazol-4- yl)phenyl]-1- ethyl-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one 55 339.4

3-(4-quinolin-8- ylphenyl)-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one 8 3-(4-quinolin-8- ylphenyl)-1-{[2- (trimethylsilyl)ethoxy]methyl}-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one

TABLE 7 Ex- am- Reffered ple Example No. MS MOLSTRUCTURE SALT NAME No.Raw Material 56 367.3

1-ethyl-3-(4- quinolin-8-ylphenyl)- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 8 3-(4-quinolin- 8-ylphenyl)-1- {[2-(trimethyl-silyl)ethoxy]methyl)- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 57399.2

1-(4-[(1-ethyl-1H- benzimidazol-2- yl)oxy]phenyl}-3,3- dimethyl-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin- 2-one 9 iodoethane 58 374.1

4-(3,3-dimethyl-2-oxo- 2,3-dihydro- 1H-pyrrolo[2,3- b]pyridin-1-yl)phenyl phenylcarbamate 9 PHENYL ISOCYANATE 59 388.2

4-(3,3-dimethyl-2- oxo-2,3-dihydro- 1H-pyrrolo[2,3- b]pyridin-1-yl)phenyl methyl(phenyl)carbamate 9 PHENYL ISOCYANATE 60 402.2

2HCl 3-[4-(1H- benzimidazol-2- yloxy)phenyl]-1- ethyl-5- methoxy-1,3-dihydro-2H- imidazo[4,5-b]pyridin 2-one 7a, 7b, 7c, 22 4-(benzyl-oxy)laniline 61 374.1

2HCl 3-[4-(1H- benzimidazol-2- yloxy)phenyl]- 7-methoxy- 1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl- oxy)laniline63 402.1

2HCl 3-[4-(1H- benzimidazo[-2- yloxy)phenyl]-1- ethyl-7-methoxy-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl-oxy)laniline

TABLE 8 Ex- Reffered ample Example No. MS MOLSTRUCTURE SALT NAME No. RawMaterial 66 362  

1-ethyl-3-[1- (1,3-thiazol-2- yl)-1H-indol- 5-yl]-1,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one 13f 2-CHLORO- THIAZOLE 67 404.3

1-ethyl-3-{2- fluoro-4-[(1- methyl-1H- benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 224-(benzyloxy)- 2-fluorolaniline 68 412.3

3-[1-(1,3- benzothiazol-2- yl)-1H-indol- 5-yl]-1-ethyl- 1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 13f 2-Chloro- benzothiazole 73 367.3

3-{4-[(5- chloropyridin-2- yl)oxy]phenyl}- 1-ethyl-1,3- dihydro-2H-imidazo[4,5-b]pyridin- 2-one 75 2,5-DICHLORO- PYRIDINE 74 401.3

1-ethyl-3-(4- {[5-(trifluoro- methyl)pyridin-2- yl]oxy}phenyl)-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 75 2-CHLORO-5- TRIFLUORO-METHYLPYRIDINE 76 412  

1-ethyl-3-{4- [(1-methyl-4-phenyl- 1H-imidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridin- 2-one 75 4-phenyl-1H-imidazole-2-thiol

TABLE 9 Ex- Reffered ample Example No. MS MOLSTRUCTURE SALT NAME No. RawMaterial 77 486.1

3-{4-[(1-{[2- (trimethyl- silyl)ethoxy]methyl}- 1H-benzimidazol-2-yl)carbonyl]phenyl}- 1,3-dihydro-2H imidazo[4,5- b]pyridin-2-one 7a, 7b,7c, 22 tert-butyl 4- aminobenzoate 78 472.1

3-[4-(1-methyl-1H- benzimidazol-4- yl)phenyl]-1-{[2- (trimethyl-silyl)ethoxy]methyl}- 1,3-dihydro-2H- imidazo[4,5-b]pyridin- 2-one 12d4-bromo-1- methyl-1H- benzimidazole 79 514.3

1-ethyl-3-{4-[(1-{[2- (trimethyl- silyl)ethoxy]methyl}-1H-benzimidazol-2- yl)carbonyl]phenyl}- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 7a, 7b, 7c, 22 tert-butyl 4- aminobenzoate 80 384.1

3-[4-(1H- benzimidazol-2- ylcarbonyl)phenyl]- 1-ethyl- 1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one 7a, 7b, 7c, 22 tert-butyl 4- aminobenzoate81 370.2

1-ethyl-3-[4-(1- methyl-1H- benzimidazol-7- yl)phenyl]- 1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 12d 7-bromo-1- methyl-1H- benzimidazole82 370.2

1-ethyl-3-[4-(1- methyl-1H- benzimidazol-4- yl)phenyl]- 1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one 12d 4-bromo-1- methyl-1H- benzimidazole 83396.2

1-ethyl-3-{4-[(1- methyl-1H- benzimidazol-2- yl)carbonyl]phenyl}-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 tert-butyl4- aminobenzoate

TABLE 10 Ex- am- Reffered ple Example No. MS MOLSTRUCTURE SALT NAME No.Raw Material 84 429.2

ethyl 3-[4-(1-ethyl- 2-oxo-1,2- dihydro-3H- imidazo[4,5- b]pyridin-3-yl)phenyl]furo[3,2- b]pyridine-6- carboxylate 12d ethyl 3-bromofuro[3,2- b]pyridine-6- carboxylate 87 443.2

ethyl 2-[4-(3,3- dimethyl-2-oxo- 2,3-dihydro-1H- pyrrolo[2,3- b]pyridin-1-yl)phenoxy] imidazo[1,2- a]pyridine-3- carboxylate 75 ethyl 2-chloroimidazo[1,2- a]pyridine-3- carboxylate 88 405.1

3-{4-[(4,5-dichloro- 1-methyl-1H- imidazol-2- yl)oxy]phenyl}-1-ethyl-1,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one 75 2,4,5-trichloro-1-methyl-1H- imidazole 89 386  

HCl 1-ethyl-3-{4-[(7- methyl-1H- benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 75 7-methyl-2-(methylsulfonyl)- 1H-benzimidazole 90 386.2

HCl 1-ethyl-3-{4-[(6- methyl-1H- benzimidazol-2- yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 75 6-methyl-2-(methylsulfonyl)- 1H-benzimidazole 91 404.2

1-ethyl-3-(4-{[1- methyl-4- (trifluoromethyl)- 1H-imidazol-2-yl]oxy}phenyl)- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 754-(trifluoro- methyl)- 1H-imidazole- 2-thiol 92 494.1

3-{4-[(4,5-dibromo- 1-methyl-1H- imidazol-2- yl)oxy]phenyl}-1-ethyl-1,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one 75 2,4,5-tribromo-1-methyl- 1H-imidazole

TABLE 11 Ex- Reffered ample Example No. MS MOLSTRUCTURE SALT NAME No.Raw Material  93 336.1

1-ethyl-3-{4- [(1-methyl-1H- imidazol-2- yl)oxy]phenyl}- 1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one 75 2-bromo-1- methyl-1H- imidazole  94358.1

1-{4-[(3-methyl- 3H-imidazo[4,5- b]pyridin-2- yl)oxy]phenyl}-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin- 2-one 5, 75 4-bromo- phenol  95396.2

1′-{4-[(3-methyl- 3H-imidazo[4,5- b]pyridin-2- yl)oxy]phenyl}spiro[cyclobutane-1,3′- pyrrolo[2,3- b]pyridin]-2′(1′H)-one 5, 75 4-bromo-phenol  96 386.2

3,3-dimethyl-1-{4- [(3-methyl-3H- imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}- 1,3-dihydro-2H- pyrrolo[2,3- b]pyridin-2-one 5, 754-bromo- phenol 104 400.3

1-ethyl-5-methyl-3- {4-[(1-methyl- 1H-benzimidazol- 2-yl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl-oxy)laniline 105 401.3

1-ethyl-5-methyl-3- {4-[(3-methyl-3H- imidazo[4,5- b]pyridin-2-yl)oxy]phenyl}- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c,22 4-(benzyl- oxy)laniline 110 420  

3-{4-[(3-bromo- 1,2,4-thiadiazol- 5-yl)oxy]phenyl}- 1-ethyl-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl-oxy)laniline

TABLE 12 Ex- am- Reffered ple Example Raw No. MS MOLSTRUCTURE SALT NAMENo. Material 111 508.2

1-ethyl-3-{4-[(1- {[2-(trimethyl- silyl)ethoxy] methyl}- 1H-thieno[3,4-d]imidazol- 2-yl)oxy]phenyl}- 1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl- oxy)laniline 113 378.1

1-ethyl-3-[4-(1H- thieno[3,4- d]imidazol-2- yloxy)phenyl]-1,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl-oxy)laniline 114 503.2

1-ethyl-3-{4-[(3- {[2-(trimethyl- silyl)ethoxy] methyl}- 3H-imidazo[4,5-c]pyridin-2- yl)oxy]phenyl}- 1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one 7a, 7b, 7c, 22 4-(benzyl- oxy)laniline 116 458.1

ethyl 2-{4-[1-(1- methylethyl)-2- oxo-1,2- dihydro-3H- imidazo[4,5-b]pyridin-3- yl]phenoxy} imidazo[1,2- a]pyridine-3- carboxylate 7a, 7b,7c, 22 4-(benzyl- oxy)laniline 117 386  

3-[4-(imidazo[1,2- a]pyridin-2- yloxy)phenyl]-1- (1-methylethyl)-1,3-dihydro-2H- imidazo[4,5- b]pyridin- 2-one 7a, 7b, 7c, 22 4-(benzyl-oxy)laniline 131 357  

1-ethyl-3-(1- pyrimidin-2-yl- 1H-indol-5-yl)- 1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one 69 2-chloro- pyrimidine

Reference Example

Examples of the compound having a PDE10A inhibitory activity include thecompounds described as Reference Examples 1-223 in the following Tables13-39. The compounds of Reference Examples 1-223 can be producedaccording to the synthetic methods described in the Examples of thepresent invention or a method analogous thereto. Furthermore, thecompounds of Reference Examples can be produced according to thesynthetic methods of the compounds described in WO2008/004117,WO2010/0057121, WO2010/57126, WO2006/072828, WO2008/001182 orWO2010/090737, or a method analogous thereto.

The compounds of Reference Examples 1-223 are useful as PDE10Ainhibitors or drugs for the prophylaxis or treatment of mental diseasessuch as schizophrenia and the like, and the administration subject,target disease, administration route, dosage form and the like are thesame as those explained for medicaments containing compound (I) or aprodrug thereof.

TABLE 13 Ref. Ex. No. compound compound name 1

1-[2-fluoro-4- (morpholin-4- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 2

1-[2-methoxy-4- (morpholin-4- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 3

1-[2-fluoro-4- (3,3,4,4- tetrafluoropyrrolidin- 1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 4

1-[2-methoxy-4- (3,3,4,4- tetrafluoropyrrolidin- 1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 5

1-[4-(4,4- difluoropiperidin-1- yl)-2-fluorophenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 6

1-[4-(4,4- difluoropiperidin-1- yl)-2- methoxyphenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 7

1-[4-(3,6-dihydro- 2H-pyran-4-yl)-2- fluorophenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 8

1-[4-(3,6-dihydro- 2H-pyran-4-yl)-2- methoxyphenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one

TABLE 14  9

1-[2-fluoro-4- (tetrahydro-2H- pyran-4-yl)phenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 10

1-[2-methoxy-4- (tetrahydro-2H- pyran-4-yl)phenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 11

1-[4-(3,3-difluoro- pyrrolidin-1-yl)- 2-fluorophenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 12

1-[4-(3,3-difluoro- pyrrolidin-1-yl)- 2-methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)- one 13

1-[2-fluoro-4-(1H- pyrazol-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 14

1-[2-methoxy-4-(1H- pyrazol-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 15

1-{4-[1-(difluoro- methyl)-1H- pyrazol-4-yl]-2- fluorophenyl}-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 16

1-{4-[1-(difluoro- methyl)-1H- pyrazol-4-yl]-2- methoxyphenyl}-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one

TABLE 15 17

1-[4-(3,5- dimethylisoxazol- 4-yl)-2- fluorophenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 18

1-[4-(3,5- dimethylisoxazol- 4-yl)-2- methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 19

1-[2-fluoro-4-(1- methyl-1H- pyrazol-4- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 20

1-[2-methoxy-4- (1-methyl-1H- pyrazol-4- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 21

1-[2-fluoro-4-(2- oxo-1,3- oxazolidin-3- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 22

1-[2-methoxy-4- (2-oxo-1,3- oxazolidin-3- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 23

1-[4-(5,5- dimethyl-2-oxo- 1,3-oxazolidin-3- yl)-2- fluorophenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 24

1-[4-(5,5- dimethyl-2-oxo- 1,3-oxazolidin-3- yl)-2- methoxyphenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 25

1-[4-(4,4- dimethyl-2-oxo- 1,3-oxazolidin-3- yl)-2- fluorophenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one

TABLE 16 26

1-[4-(4,4- dimethyl-2-oxo- 1,3-oxazolidin-3- yl)-2- methoxyphenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 27

1-[2-fluoro-4-(2- oxopyrrolidin-1- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 28

1-[2-methoxy-4- (2-oxopyrrolidin- 1-yl)phenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 29

1-[4-(4,4- dimethyl-2- oxopyrrolidin-1- yl)-2- fluorophenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 30

1-[4-(4,4- dimethyl-2- oxopyrrolidin-1- yl)-2- methoxyphenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 31

1-[4-(2,2- dimethyl-5- oxopyrrolidin-1- yl)-2- fluorophenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 32

1-[4-(2,2- dimethyl-5- oxopyrrolidin-1- yl)-2- methoxyphenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 33

1-[4-(3,3- dimethyl-2- oxopyrrolidin-1- yl)-2- fluorophenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 34

1-[4-(3,3- dimethyl-2- oxopyrrolidin-1- yl)-2- methoxyphenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one

TABLE 17 35

1-[2-fluoro-4-(3- methyl-2- oxopyrrolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 36

1-[2-methoxy-4-(3- methyl-2- oxopyrrolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 37

1-[2-fluoro-4-(2- methyl-5- oxopyrrolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 38

1-[2-methoxy-4-(2- methyl-5- oxopyrrolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 39

6-{3-fluoro-4-[4- oxo-3-(1-phenyl- 1H-pyrazol-5- yl)pyridazin-1(4H)-yl]phenyl}-4-oxa-6- azaspiro[2,4]heptan- 5-one 40

6-{3-methoxy-4-[4- oxo-3-(1-phenyl- 1H-pyrazol-5- yl)pyridazin-1(4H)-yl]phenyl}-4-oxa-6- azaspiro[2,4]heptan- 5-one 41

1-[4-(3-tert-butyl-2- oxoimidazolidin-1- yl)-2-fluorophenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin-4(1H)- one 42

1-[4-(3-tert-butyl-2- oxoimidazolidin-1- yl)-2- methoxyphenyl]-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin-4(1H)- one

TABLE 18 43

1-[2-fluoro-4-(2- oxoimidazolidin-1- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one 44

1-[2-methoxy-4-(2- oxoimidazolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 45

1-[2-fluoro-4-(3- methyl-2-oxo- imidazolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 46

1-[2-methoxy-4-(3- methyl-2-oxo- imidazolidin-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin- 4(1H)-one 47

1-{4-[3-(difluoro- methyl)-2-oxo- imidazolidin-1-yl]- 2-fluorophenyl}-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin-4(1H)- one 48

1-{4-[3-(difluoro- methyl)-2-oxo- imidazolidin-1-yl]- 2-methoxyphenyl}-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin-4(1H)- one 49

1-[4-(4-chloro-1H- pyrazol-1-yl)-2- fluorophenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 50

1-[4-(4-chloro-1H- pyrazol-1-yl)-2- methoxyphenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one

TABLE 19 51

1-[2-fluoro-4-(4- fluoro-1H-pyrazol- 1-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 52

1-[4-(4-fluoro-1H- pyrazol-1-yl)-2- methoxyphenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 53

1-[2-fluoro-4-(5- hydroxy-1H- pyrazol-1- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 54

1-[4-(5-hydroxy- 1H-pyrazol-1-yl)- 2-methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 55

1-{4-[5- (difluoromethoxy)- 1H-pyrazol-1-yl]- 2-fluorophenyl}-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 56

1-{4-[5- (difluoromethoxy)- 1H-pyrazol-1-yl]- 2- methoxyphenyl}-3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 57

1-{4-[2- (difluoromethyl)- 5-oxo-2,5-dihydro- 1H-pyrazol-1-yl]-2-fluorophenyl}-3- (1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one 58

1-{4-[2- (difluoromethyl)- 5-oxo-2,5-dihydro- 1H-pyrazol-1-yl]- 2-methoxyphenyl}- 3-(1-phenyl-1H- pyrazol-5- yl)pyridazin- 4(1H)-one

TABLE 20 59

1-[2-fluoro-4- (1H-pyrrol-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 60

1-[2-methoxy-4- (1H-pyrrol-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 61

1-[4-(3,4- difluoro-1H- pyrrolo-1-yl)-2- fluorophenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 62

1-[4-(3,4- difluoro-1H- pyrrolo-1-yl)-2- methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 63

1-[2-fluoro-4- (1,3-oxazol-2- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 64

1-[2-methoxy-4- (1,3-oxazol-2- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 65

1-[2-fluoro-4- (1,3-thiazol-2- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 66

1-[2-methoxy-4- (1,3-thiazol-2- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 67

1-[2-fluoro-4- (1H-imidazol-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one

TABLE 21 68

1-[4-(1H-imidazol-1-yl)-2- methoxyphenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 69

1-{2-fluoro-4-[3- (trifluoromethyl)pyrrolidin- 1-yl]phenyl}-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one 70

1-{2-methoxy-4-[3- (trifluoromethyl)pyrrolidin-1-yl]phenyl}-3-(1-phenyl- 1H-pyrazol-5-yl)pyridazin- 4(1H)-one 71

1-[4-(2,5-dihydro-1H- pyrrolo-1-yl)-2- fluorophenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one 72

1-[4-(2,5-dihydro-1H- pyrrolo-1-yl)-2- methoxyphenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 73

1-[4-(3,3-difluoropiperidin- 1-yl)-2-fluorophenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 74

1-[4-(3,3-difluoropiperidin- 1-yl)-2-methoxyphenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 75

4-{3-fluoro-4-[4-oxo-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin-1(4H)-yl]phenyl}morpholin-3-one 76

4-{3-methoxy-4-[4-oxo-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin-1(4H)-yl]phenyl}morpholin-3-one

TABLE 22 77

1-[4-(3,3- difluoroazetidin- 1-yl)-2- fluorophenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 78

1-[4-(3,3- difluoroazetidin- 1-yl)-2- methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 79

1-[2-fluoro-4-(3- fluoroazetidin-1- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 80

1-[4-(3- fluoroazetidin-1- yl)-2- methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 81

1-[2-fluoro-4-(2- oxoazetidin-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 82

1-[2-methoxy-4- (2-oxoazetidin-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 83

1-[4-(3,3- difluoropiperidin- 1-yl)-2- fluorophenyl]-3- (1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 84

1-[4-(3,3- difluoropiperidin- 1-yl)-2- methoxyphenyl]- 3-(1-phenyl-1H-pyrazol-5- yl)pyridazin- 4(1H)-one 85

1-(4-cyclopropyl- 2-fluorophenyl)- 3-(1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one

TABLE 23 86

1-(4-cyclopropyl-2- methoxyphenyl)-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 87

1-[2-fluoro-4-(pyridin- 2-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 88

1-[2-methoxy-4-(pyridin- 2-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 89

1-[2-fluoro-4-(pyridin- 3-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 90

1-[2-methoxy-4-(pyridin- 3-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 91

1-[2-fluoro-4-(pyridin- 4-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 92

1-[2-methoxy-4-(pyridin- 4-yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 93

1-{4-[(2R,6S)-2,6- dimethylmorpholin-4- yl]-2-fluorophenyl}-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one 94

1-{4-[(2R,6S)-2,6- dimethylmorpholin-4- yl]-2-methoxyphenyl}-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one

TABLE 24  95

1-[2-fluoro-4-(8-oxa-3- azabicyclo[3.2.1]octa-3- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one  96

1-[2-methoxy-4-(8-oxa-3- azabicyclo[3.2.1]octa-3-yl)phenyl]-3-(1-phenyl- 1H-pyrazol-5- yl)pyridazin-4(1H)-one  97

1-[2-fluoro-4-(1,4- oxazepan-4-yl)phenyl]- 3-(1-phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one  98

1-[2-methoxy-4-(1,4- oxazepan-4-yl)phenyl]- 3-(1-phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one  99

1-{4-[5-(cyclopropyl- methoxy)-1H-pyrazol- 1-yl]-2-fluorophenyl}-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one 100

1-{4-[5-(cyclopropyl- methoxy)-1H-pyrazol- 1-yl]-2-methoxyphenyl}-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one 101

1-{2-fluoro-4-[5-(2,2,2- trifluoroethoxy)-1H- pyrazol-1-yl]phenyl}-3-(1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 102

1-{2-methoxy-4-[5-(2,2,2- trifluoroethoxy)-1H- pyrazol-1-yl]phenyl}-3-(1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 103

1-[2-fluoro-4-(5-methoxy- 1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one

TABLE 25 104

1-[2-methoxy-4-(5-methoxy- 1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 105

1-[2-fluoro-4-(4-hydroxy-4- methylpiperidin-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 106

1-[4-(4-hydroxy-4- methylpiperidin-1-yl)-2- methoxyphenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one 107

1-[2-fluoro-4-(pyrimidin-2- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 108

1-[2-methoxy-4-(pyrimidin-2- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 109

1-[2-fluoro-4-(pyrazin-2- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 110

1-[2-methoxy-4-(pyrazin-2- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 111

1-[2-fluoro-4-(pyrimidin-5- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one

TABLE 26 112

1-[2-methoxy-4- (pyrimidin-5- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one 113

1-[2-fluoro-4- (pyrimidin-4- yl)phenyl]-3- (1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 114

1-[2-methoxy-4- (pyrimidin-4- yl)phenyl]-3- (1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 115

1-[2-fluoro-4- (pyridazin-3- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 116

1-[2-methoxy-4- (pyridazin-3- yl)phenyl]-3- (1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 117

1-[2-fluoro-3-(1H- pyrazol-1- yl)phenyl]-3-(1- phenyl-1H-pyrazol-5-yl)pyridazin- 4(1H)-one 118

1-[2-methoxy-3- (1H-pyrazol-1- yl)phenyl]-3-(1- phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 119

1-[2-fluoro-5-(1H- pyrazol-1- yl)phenyl]-3- (1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one 120

1-[2-methoxy-5-(1H- pyrazol-1-yl)phenyl]- 3-(1-phenyl-1H- pyrazol-5-yl)pyridazin- 4(1H)-one

TABLE 27 121

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one 122

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one 123

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 124

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 125

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 126

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 127

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 128

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 129

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]pyridazin-4(1H)-one

TABLE 28 130

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]pyridazin-4(1H)-one 131

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 132

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 133

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-{3-methyl-1-[3-trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 134

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 135

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-(4-methyl-1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 136

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-(4-methyl-1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 137

3-[1-(3-chlorophenyl)-4-methyl- 1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]pyridazin-4(1H)-one

TABLE 29 138

3-[1-(3-chlorophenyl)-4-methyl- 1H-pyrazol-5-yl]-1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]pyridazin-4(1H)-one 139

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 140

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 141

1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-{4-methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 142

1-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3-{4-methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 143

1-[2-chloro-4-(1H-pyrazol-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 144

3-(1-phenyl-1H-pyrazol-5-yl)-1- [4-(1H-pyrazol-1-yl)-2-(trifluoromethyl)phenyl]pyridazin- 4(1H)-one 145

3-(1-phenyl-1H-pyrazol-5-yl)-1- [4-(1H-pyrazol-1-yl)-2-(trifluoromethoxy)phenyl]pyridazin- 4(1H)-one 146

1-[2-ethoxy-4-(1H-pyrazol-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one

TABLE 30 147

1-[2-(difluoromethoxy)-4-(1H- pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 148

1-[2-(cyclopropylmethoxy)-4-(1H- pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 149

1-[2-methyl-4-(1H-pyrazol-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 150

1-[2-ethyl-4-(1H-pyrazol-1- yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 151

1-[2-(1-methylethyl)-4-(1H- pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 152

1-[2-fluoro-4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)phenyl]-3-(1-phenyl-1H- pyrazol-5-yl)pyridazin-4(1H)-one 153

1-[2-methoxy-4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)phenyl]-3-(1-phenyl-1H- pyrazol-5-yl)pyridazin-4(1H)-one 154

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]pyridazin- 4(1H)-one 155

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[2-methoxy-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]pyridazin- 4(1H)-one

TABLE 31 156

1-[2-fluoro-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 157

1-[2-methoxy-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 158

1-[2-fluoro-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 159

1-[2-methoxy-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 160

1-[2-fluoro-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 161

1-[2-methoxy-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 162

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3- yl)phenyl]pyridazin-4(1H)-one 163

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[2-methoxy-4-(2-oxo-1,3-oxazolidin-3- yl)phenyl]pyridazin-4(1H)-one

TABLE 32 164

1-[2-fluoro-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{3- methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 165

1-[2-methoxy-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{3- methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 166

1-[2-fluoro-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{3- methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 167

1-[2-methoxy-4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-3-{3- methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 168

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2- fluorophenyl}pyridazin-4(1H)-one 169

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2- methoxyphenyl}pyridazin-4(1H)-one 170

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-fluorophenyl}-3-{1-[3-(trifluoromethyl)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one 171

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-methoxyphenyl}-3-{1-[3-(trifluoromethyl)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one

TABLE 33 172

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-fluorophenyl}-3-{1-[3-(trifluoromethoxy)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one173

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-methoxyphenyl}-3-{1-[3-(trifluoromethoxy)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one174

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-fluorophenyl}-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 175

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-methoxyphenyl}-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 176

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-{4-[1-(difluoromethyl)-1H-pyrazol-4- yl]-2-fluorophenyl}pyridazin- 4(1H)-one177

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-{4-[1-(difluoromethyl)-1H-pyrazol-4- yl]-2-methoxyphenyl}pyridazin- 4(1H)-one178

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-fluorophenyl}-3-{3-methyl-1-[3- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one

TABLE 34 179

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-methoxyphenyl}-3-{3-methyl-1-[3- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 180

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-fluorophenyl}-3-{3-methyl-1-[3- (trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 181

1-{4-[1-(difluoromethyl)-1H- pyrazol-4-yl]-2-methoxyphenyl}-3-{3-methyl-1-[3- (trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 182

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2- fluorophenyl]pyridazin-4(1H)-one 183

3-[1-(3-chlorophenyl)-1H-pyrazol- 5yl]-1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2- methoxyphenyl]pyridazin-4(1H)-one 184

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-fluorophenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 185

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-methoxyphenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 186

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-fluorophenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one

TABLE 35 187

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-methoxyphenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 188

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-fluorophenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 189

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-methoxyphenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 190

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2- fluorophenyl]pyridazin-4(1H)-one 191

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2- methoxyphenyl]pyridazin-4(1H)-one 192

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-fluorophenyl]-3-{3-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 193

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-methoxyphenyl]-3-{3-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 194

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-fluorophenyl]-3-{3-methyl-1-[3-(trifluoromethoxy)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one

TABLE 36 195

1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-methoxyphenyl]-3-{3-methyl-1-[3-(trifluoromethoxy)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one 196

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-{4-[5-(difluoromethoxy)-1H-pyrazol-1-yl]-2- fluorophenyl}pyridazin-4(1H)-one 197

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-{4-[5-(difluoromethoxy)-1H-pyrazol-1-yl]-2- methoxyphenyl}pyridazin-4(1H)-one 198

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-fluorophenyl}-3-{1-[3-(trifluoromethyl)phenyl]- 1H-pyrazol-5-yl)pyridazin-4(1H)- one 199

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-methoxyphenyl}-3-{1-[3-(trifluoromethyl)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one 200

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-fluorophenyl}-3-{1-[3-(trifluoromethoxy)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one201

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-methoxyphenyl}-3-{1-[3-(trifluoromethoxy)phenyl]- 1H-pyrazol-5-yl}pyridazin-4(1H)- one202

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-fluorophenyl}-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one 203

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-methoxyphenyl}-3-(3-methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one

TABLE 37 204

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-{4-[5-(difluoromethoxy)-1H-pyrazol-1- yl]-2-fluorophenyl}pyridazin- 4(1H)-one205

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-{4-[5-(difluoromethoxy)-1H-pyrazol-1- yl]-2-methoxyphenyl}pyridazin- 4(1H)-one206

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-fluorophenyl}-3-{3-methyl-1-[3- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 207

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-methoxyphenyl}-3-{3-methyl-1-[3- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 208

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-fluorophenyl}-3-{3-methyl-1-[3- (trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 209

1-{4-[5-(difluoromethoxy)-1H- pyrazol-1-yl]-2-methoxyphenyl}-3-{3-methyl-1-[3- (trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one 210

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[2-fluoro-4-(pyridin-2-yl)phenyl]pyridazin-4(1H)-one 211

3-[1-(3-chlorophenyl)-1H-pyrazol- 5-yl]-1-[2-methoxy-4-(pyridin-2-yl)phenyl]pyridazin-4(1H)-one

TABLE 38 212

1-[2-fluoro-4-(pyridin-2- yl)phenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 213

1-[2-methoxy-4-(pyridin-2- yl)phenyl]-3-{1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 214

1-[2-fluoro-4-(pyridin-2- yl)phenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl)pyridazin-4(1H)-one 215

1-[2-methoxy-4-(pyridin-2- yl)phenyl]-3-{1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 216

1-[2-fluoro-4-(pyridin-2- yl)phenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 217

1-[2-methoxy-4-(pyridin-2- yl)phenyl]-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one 218

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[2-fluoro-4-(pyridin-2-yl)phenyl]pyridazin- 4(1H)-one 219

3-[1-(3-chlorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1-[2-methoxy-4-(pyridin-2-yl)phenyl]pyridazin- 4(1H)-one 220

1-[2-fluoro-4-(pyridin-2- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one

TABLE 39 221

1-[2-methoxy-4-(pyridin-2- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 222

1-[2-fluoro-4-(pyridin-2- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one 223

1-[2-methoxy-4-(pyridin-2- yl)phenyl]-3-{3-methyl-1-[3-(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)-one

Test Example 1 PDE Enzyme Inhibition

Human PDE10A enzyme was generated from Sf9 or COS-7 cells transfectedwith the full-length gene. Cloned enzyme was extracted from homogenizedcell pellets. The extracted enzyme from sf9 cells was partially purifiedusing His-tag affinity column. The enzyme was stored at −70° C. untiluse. PDE activity was measured using a SPA (Scintillation ProximityAssay) (GE Healthcare). To evaluate the inhibitory activity, 10 μL ofserial diluted compounds were incubated with 20 μL of PDE enzyme inassay buffer (50 mM HEPES-NaOH, 8.3 mM MgCl₂, 1.7 mM EGTA, 0.1% BSA (pH7.4)) for 30 min. at room temperature. Final concentration of DMSO inthe assay was 1 percent as compounds were tested in duplicate in 96-wellhalf-area plates (Corning). To start the reaction, 10 μL of substrate[³H] cGMP (25 or 50 nM; enclosed in SPA kits from GE Healthcare orpurchased from PerkinElmer, respectively) was added for a final assayvolume of 40 μL. After 60 min incubation at room temperature, yttriumSPA beads containing Zinc sulphate were added (20 μL at 6 mg/mL) toterminate the PDE reaction. After being settled for 60 min, assay plateswere counted in a scintillation counter (PerkinElmer) to allowcalculation of inhibition rate. Inhibition rate was calculated on thebasis of 0% control wells with DMSO and 100% control wells withoutenzyme. The results are shown in Table 40.

TABLE 40 Percent Percent Percent Ex. inhibition inhibition inhibitionNo. (10 μM) (1 μM) (0.1 μM) 1 100 98 2 103 104 3 99 8 98 9 99 99 12 9993 13 101 100 24 98 27 102 31 98 99 39 101 100 40 101 99 48 100 96 64101 100 65 101 100 71 97 99 72 110 104 75 101 98 85 99 95 86 98 97 97 9897 98 101 99 99 105 100 100 100 99 101 99 101 102 106 99 103 103 101 106102 103 107 102 103 108 102 100 109 102 99 112 98 99 115 97 100 118 104102 119 103 99 120 106 109 121 99 103 122 107 109 123 101 96 124 99 99125 101 99 126 100 98 127 101 101 128 91 94 129 96 89 130 98 95 132 107104 133 101 104 134 104 101 135 99 94 136 98 81 137 98 88 138 105 93

Test Example 2 (1) Animals

Male ICR mice were supplied by CLEA Japan, Inc (Japan). After arrival tothe vivarium, animals were allowed more than 1 week for acclimation.They were housed under a 12 h-12 h light/dark cycle in a temperature-and humidity-controlled laboratory and allowed food and water adlibitum. The care and use of the animals and the experimental protocolsused in this research were approved by the Experimental Animal Care andUse Committee of Takeda Pharmaceutical Company, Ltd (Osaka, Japan).

(2) Drug Administration

The compounds were suspended in 0.5% (w/v) methylcellulose in distilledwater, and the suspension was administered by orally. MK-801 hydrogenmaleate((5R,10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminemaleate, Sigma-Aldrich, St Louis, Mo.) was dissolved in saline, andadministered subcutaneously (s.c.). All drugs were dosed in a volume of20 mL/kg body weight for mice.

(3) Measurement of Striatal Tissue Cyclic Nucleotides

Male ICR mice (28-42 g) were sacrificed by focused microwave irradiationof the brain at 60 min after administration of the compounds. Striatumwere isolated and homogenized in 0.5 N HCl followed by centrifugation.Supernatant concentrations of cyclic nucleotides were measured usingenzyme immunoassay kits (Cayman Chemical, Ann Arbor, Mich.). Values wereexpressed as the percentage of the average of the vehicle-treatedsamples. All data were represented as means plus the standard errors ofthe means (n=8). The variance of data was judged by Bartlett's test. Thestatistical significance was determined by the Dunnett's t-test (forhomogenous data) or the Steel's test (for non-homogenous data) withsignificance set at #P<0.05.

(4) Inhibition of MK-801-induced hyperlocomotion

The widely used animal models of psychosis have been the measurement ofthe extent of hyperlocomotion induced by psychostimulants (e.g.,amphetamine, cocaine, methamphetamine, MK-801 and phencyclidine) inrodents (Schizophrenia Bulletin 2010, vol. 36: 1066-1072;Psychopharmacology 1999, vol. 145: 237-250). The compounds were testedfor its ability to antagonize MK-801-induced hyperlocomotion in mice.Male ICR mice (28-42 g) were habituated to the locomotor chambers withinfrared sensors (Brain Science Idea Co., Ltd. Japan) for more than 60min. Animals were removed from each chamber and treated with eithervehicle or test compounds (p.o.) and immediately returned to thechamber. After 60 min, animals were again removed from the chambers andtreated with either saline or MK-801 (0.3 mg/kg, s.c.), and thenimmediately returned to the test chamber. Activity count was recordedevery 1 min bins. Total amounts of activity were measured during 120 minafter MK-801 treatment. Data were represented as means plus the standarderrors of the means (n=8-9). Statistical analysis was performed with theWelch's t-test for comparison between control group and MK-801+vehicletreated group with significance set at ***P<0.001 and the Dunnett's testfor comparisons with vehicle-treated group with significance set at#P<0.05.

Compounds in Figures (FIG. 1 and FIG. 2) correspond to the compounds ofthe following Examples.

Compound A: Example 118

Compound B: Example 119

Compound C: Example 120

Compound D: Example 122

Compound E: Example 133

Compound F: Example 135

Compound G: Example 138

Formulation Example 1

(1) Compound of Example 1 10.0 g (2) Lactose 70.0 g (3) Cornstarch 50.0g (4) Soluble starch  7.0 g (5) Magnesium stearate  3.0 g

After 10.0 g of the compound of Example 1 and 3.0 g of magnesiumstearate are granulated in 70 mL aqueous solution of soluble starch (7.0g as soluble starch) and then dried, the resulting mixture is mixed with70.0 g of lactose and 50.0 g of cornstarch (lactose, cornstarch, solublestarch and magnesium stearate are all products in compliance withJapanese Pharmacopoeia 14^(th) Edition). The mixture is compressed toobtain a tablet.

The invention claimed is: 1.1-Ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof.
 2. A pharmaceutical composition comprising1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,or a salt thereof, and a pharmaceutically acceptable carrier.